Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which is expressed anti-apoptotic Bcl-xL protein.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.13/649,950, filed Oct. 11, 2012, which claims priority to U.S.Provisional Application No. 61/547,165, filed Oct. 14, 2011, each ofwhich are incorporated by reference in its entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which inhibit the activity ofBcl-xL anti-apoptotic proteins, compositions containing the compounds,and methods of treating diseases during which anti-apoptotic Bcl-xLproteins are expressed.

BACKGROUND OF THE INVENTION

Apoptosis is recognized as an essential biological process for tissuehomeostasis of all living species. In mammals in particular, it has beenshown to regulate early embryonic development. Later in life, cell deathis a default mechanism by which potentially dangerous cells (e.g., cellscarrying cancerous defects) are removed. Several apoptotic pathways havebeen uncovered, and one of the most important involves the Bcl-2 familyof proteins, which are key regulators of the mitochondrial (also called“intrinsic”) pathway of apoptosis. See, Danial, N. N. and Korsmeyer, S.J. Cell (2004) 116, 205-219. The structural homology domains BH1, BH2,BH3 and BH4 are characteristic of this family of proteins. The Bcl-2family of proteins can be further classified into three subfamiliesdepending on how many of the homology domains each protein contains andon its biological activity (i.e., whether it has pro- or anti-apoptoticfunction).

The first subgroup contains proteins having all 4 homology domains,i.e., BH1, BH2, BH3 and BH4. Their general effect is anti-apoptotic,that is to preserve a cell from starting a cell death process. Proteinssuch as, for example, Bcl-2, Bcl-w, Bcl-xL, Mcl-1 and Bfl-1/A1 aremembers of this first subgroup. Proteins belonging to the secondsubgroup contain the three homology domains BH1, BH2 and BH3, and have apro-apoptotic effect. The two main representative proteins of thissecond subgroup are Bax and Bak. Finally, the third subgroup is composedof proteins containing only the BH3 domain and members of this subgroupare usually referred to as “BH3-only proteins.” Their biological effecton the cell is pro-apoptotic. Bim, Bid, Bad, Bik, Noxa, Hrk, Bmf, andPuma are examples of this third subfamily of proteins. The exactmechanism by which the Bcl-2 family proteins regulate cell death isstill not entirely known and understanding this mechanism is an activearea of research in the science community. In one hypothesis ofregulation of cell death by Bcl-2 family proteins, the BH3-only proteinsare further categorized as either “activator” (e.g., Bim and Bid) or“sensitizer” (e.g., Bad, Bik, Noxa, Hrk, Bmf, and Puma) proteinsdepending on their regulatory function.

The key to tissue homeostasis is achieving the delicate balance in theinteractions among the three subgroups of protein in cells. Recentstudies have tried to elucidate the mechanisms by which pro-apoptoticand anti-apoptotic subgroups of Bcl-2 family proteins interact to allowa cell to undergo programmed cell death. After receiving intra- orextra-cellular signals in cells, post-translational or transcriptionalactivation of BH3-only proteins occurs. The BH3-only proteins are theprimary inducers of an apoptotic cascade that includes, as one step, theactivation of the pro-apoptotic proteins Bax and Bak on themitochondrial membrane in cells. Upon activation of Bax and/or Bak thatare either already anchored to the mitochondrial membrane or migrate tothis membrane, Bax and/or Bak oligomerize to result in mitochondrialouter membrane permeabilization (MOMP), the release of cytochrome C, anddownstream activation of effector caspases, to ultimately result in cellapoptosis. Some researchers hypothesize that certain BH3-only proteins(e.g., Puma, Bim, Bid) are “activators” in that these proteins directlyengage pro-apoptotic proteins Bax and Bak to initiate MOMP, while otherBH3-only proteins (e.g., Bad, Bik and Noxa) are “sensitizers” and induceBax and Bak oligomerization indirectly by binding anti-apoptoticproteins (e.g., Bcl-2, Bcl-xL, Bcl-w, Mcl-1) and displacing and“freeing-up” the “activator” BH3-only proteins, which subsequently bindto and activate pro-apoptotic proteins (e.g., Bax, Bak) to induce celldeath. Other researchers suggest that anti-apoptotic proteins engage andseqeuester Bax and Bak directly and all BH3-only proteins regulates thisinteraction by binding to anti-apoptotic proteins (e.g., Bcl-2, Bcl-xL,Bcl-w, Mcl-1) which results in the release Bax and Bak. See, Adams, J.M. and Cory S. Oncogene (2007) 26, 1324-1337; Willis, S. N. et al.Science (2007) 315, 856-859. Although the exact interactions throughwhich the anti- and pro-apoptotic Bcl-2 family proteins regulateapoptosis remain under debate, there is a large body of scientificevidence to show that compounds which inhibit the binding of BH3-onlyproteins to anti-apoptotic Bcl-2 family proteins promote apoptosis incells.

Dysregulated apoptotic pathways have been implicated in the pathology ofmany significant diseases such as neurodegenerative conditions(up-regulated apoptosis), such as for example, Alzheimer's disease; andproliferative diseases (down-regulated apoptosis) such as for example,cancer, autoimmune diseases and pro-thrombotic conditions.

In one aspect, the implication that down-regulated apoptosis (and moreparticularly the Bcl-2 family of proteins) is involved in the onset ofcancerous malignancy has revealed a novel way of targeting this stillelusive disease. Research has shown, for example, the anti-apoptoticproteins, Bcl-2 and Bcl-xL, are over-expressed in many cancer celltypes. See, Zhang J. Y., Nature Reviews/Drug Discovery, (2002) 1, 101;Kirkin, V. et al. Biochimica et Biophysica Acta (2004) 1644, 229-249;and Amundson, S. A. et al. Cancer Research (2000) 60, 6101-6110. Theeffect of this deregulation is the survival of altered cells which wouldotherwise have undergone apoptosis in normal conditions. The repetitionof these defects associated with unregulated proliferation is thought tobe the starting point of cancerous evolution. Additionally, research hasshown that BH3-only proteins can act as tumor suppressors when expressedin diseased animals.

These findings as well as numerous others have made possible theemergence of new strategies in drug discovery for targeting cancer. If asmall molecule that could mimic the effect of BH3-only proteins wereable to enter the cell and overcome the anti-apoptotic proteinover-expression, then it could be possible to reset the apoptoticprocess. This strategy can have the advantage that it can alleviate theproblem of drug resistance which is usually a consequence of apoptoticderegulation (abnormal survival).

Researchers also have demonstrated that platelets also contain thenecessary apoptotic machinery (e.g., Bax, Bak, Bcl-xL, Bcl-2, cytochromec, caspase-9, caspase-3 and APAF-1) to execute programmed cell deaththrough the intrinsic apoptotic pathway. Although circulating plateletproduction is a normal physiological process, a number of diseases arecaused or exacerbated by excess of, or undesired activation of,platelets. The above suggests that therapeutic agents capable ofinhibiting anti-apoptotic proteins in platelets and reducing the numberof platelets in mammals maybe useful in treating pro-thromboticconditions and diseases that are characterized by an excess of, orundesired activation of, platelets.

We have developed a class of small molecule BH3-only protein mimetics,i.e., ABT-737 and ABT-263, that bind strongly to a subset ofanti-apoptotic Bcl-2 proteins including Bcl-2, Bcl-w and Bcl-xL, butonly weakly to Mcl-1 and A1, and exhibits mechanism-based cytotoxicity.These compounds were tested in animal studies and demonstrated cytotoxicactivity in certain xenograft models as single agents, as well asenhanced the effects of a number of chemotherapeutic agents on otherxenograft models when used in combination. See, Tse, C. et al. CancerRes (2008) 68, 3421-3428; and van Delft, M. F. et al. Cancer Cell (2006)10, 389-399. These in vivo studies suggest the potential utility ofinhibitors of anti-apoptotic Bcl-2 family proteins for the treatment ofdiseases that involve a dysregulated apoptotic pathway.

The natural expression levels of anti-apoptotic Bcl-2 family proteinsmembers vary in different cell types. For example, in young platelets,Bcl-xL protein is highly expressed and plays an important role inregulating cell death (life span) of platelets. Also, in certain cancercell types, the cancer cell's survival is attributed to thedysregulation of the apoptotic pathway caused by the over-expression ofone or more anti-apoptotic Bcl-2 protein family members. In view of theimportant role for Bcl-2 family of proteins in regulating apoptosis inboth cancerous and normal (i.e., non-cancerous) cells, and therecognized inter-cell type variability of Bcl-2 family proteinexpression, it is advantageous to have a small molecule inhibitor thatselectively targets and preferably binds to one type or a subset ofanti-apoptotic Bcl-2 protein(s), for example, to an anti-apoptotic Bcl-2family member that overexpressed in a certain cancer type. Such aselective compound also may confer certain advantages in the clinicalsetting, by providing, for example, the flexibility to select a dosingregimen, a reduced on-target toxic effect in normal cells, among others(e.g., lymphopenia has been observed in Bcl-2 deficient mice). See,Nakayama, K. et al. PNAS (1994) 91, 3700-3704.

In view of the above, there is a need in the art for small moleculestherapeutics that can selectively inhibit the activity of one type or asubset of anti-apoptotic Bcl-2 proteins, for example, of a Bcl-xLanti-apoptotic protein. The present invention fulfills at least thisneed.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (I)

or a therapeutically acceptable salt thereof, wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

Y¹ is phenylene, or C₅₋₆ heteroarylene; optionally fused to one or tworings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y¹ is optionally substituted with one, two,three, or four substituents independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵) NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸, OC(O)OR)⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, or 2.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl.

In another embodiment of Formula (I), Y¹ is pyridinyl or phenyl.

In another embodiment of Formula (I), X is benzo[d]thiazolyl; which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, or triazolyl, andX is benzo[d]thiazolyl; which is optionally substituted with one, two,three or four R⁴. In another embodiment of Formula (I), Y¹ is pyridinylor phenyl, and X is benzo[d]thiazolyl; which is optionally substitutedwith one, two, three or four R⁴.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl; and Z¹ is

In another embodiment of Formula (I), Y¹ is pyridinyl or phenyl; and Z¹is

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl; L¹ is (CR⁶R⁷)_(q); and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, C₅₋₆heteroaryl, and C₃₋₇ heterocycloalkyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3. In anotherembodiment of Formula (I), Y¹ is pyridinyl or phenyl; L¹ is (CR⁶R⁷)_(q);and Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, C₅₋₆ heteroaryl, and C₃₋₇ heterocycloalkyl;wherein R⁶ and R⁷, at each occurrence, are R¹⁵ or hydrogen; and q is 1,2, or 3.

In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl, ortriazolyl; L¹ is selected from the group consisting of(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r); s is 0; r is 0 or 1; R^(6A) isindependently selected from the group consisting of hydrogen, and C₁₋₆alkyl; and R⁶ and R⁷, at each occurrence, are hydrogen. In anotherembodiment of Formula (I), Y¹ is pyridinyl or phenyl; L¹ is selectedfrom the group consisting of (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); s is 0; r is 0 or 1; R^(6A) isindependently selected from the group consisting of hydrogen, and C₁₋₆alkyl; and R⁶ and R⁷, at each occurrence, are hydrogen.

Still another embodiment pertains to a compound having Formula (I),selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{4-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(5,6-difluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(7-chloro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-cyano-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-carboxy-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,4-dihydro-2H-chromen-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-{[3-(dimethylamino)propyl]amino}-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(pyridin-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)prop-1-yn-1-yl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,33-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,33-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-phenylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro    isoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4,4-difluorocyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(diphenylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(morpholin-4-yl)-1-phenylpropyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[3-(morpholin-4-yl)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methylpropyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(2-methoxyethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,3-dimethylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(1,4-dioxan-2-ylmethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-carboxy-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(piperidin-1-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6,6′-bis[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3′-bipyridine-2,2′-dicarboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-methoxymethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,3-dimethyl-1-(morpholin-4-yl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[1-cyclohexyl-3-(morpholin-4-yl)propyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-5-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[3-(morpholin-4-yl)propoxy]cycloheptyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   N-1,3-benzothiazol-2-yl)-2-(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxycyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({1-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-hydroxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dimethoxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{([1-(1,4-dioxan-2-ylmethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(morpholin-4-yl)-2-oxoethoxy]cyclohexyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dihydroxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(dimethylamino)cyclohexyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-({1-[1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylamino)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of acompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

Unless otherwise defined herein, scientific and technical terms used inconnection with the present invention shall have the meanings that arecommonly understood by those of ordinary skill in the art. The meaningand scope of the terms should be clear, however, in the event of anylatent ambiguity, definitions provided herein take precedent over anydictionary or extrinsic definition. In this application, the use of “or”means “and/or” unless stated otherwise. Furthermore, the use of the term“including”, as well as other forms, such as “includes” and “included”,is not limiting. With reference to the use of the words “comprise” or“comprises” or “comprising” in this patent application (including theclaims), Applicants note that unless the context requires otherwise,those words are used on the basis and clear understanding that they areto be interpreted inclusively, rather than exclusively, and thatApplicants intend each of those words to be so interpreted in construingthis patent application, including the claims below. For a variable thatoccurs more than one time in any substituent or in the compound of theinvention or any other formulae herein, its definition on eachoccurrence is independent of its definition at every other occurrence.Combinations of substituents are permissible only if such combinationsresult in stable compounds. Stable compounds are compounds which can beisolated in a useful degree of purity from a reaction mixture.

It is meant to be understood that proper valences are maintained for allcombinations herein, that monovalent moieties having more than one atomare attached through their left ends, and that divalent moieties aredrawn from left to right.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkyl” (alone or in combination with another term(s)) means astraight- or branched-chain saturated hydrocarbyl substituent typicallycontaining from 1 to about 10 carbon atoms; or in another embodiment,from 1 to about 8 carbon atoms; in another embodiment, from 1 to about 6carbon atoms; and in another embodiment, from 1 to about 4 carbon atoms.Examples of such substituents include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,and hexyl and the like.

The term “alkenyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore double bonds and typically from 2 to about 10 carbon atoms; or inanother embodiment, from 2 to about 8 carbon atoms; in anotherembodiment, from 2 to about 6 carbon atoms; and in another embodiment,from 2 to about 4 carbon atoms. Examples of such substituents includeethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl,1,4-butadienyl, 1-butenyl, 2-butenyl, and 3-butenyl and the like.

The term “alkynyl” (alone or in combination with another term(s)) meansa straight- or branched-chain hydrocarbyl substituent containing one ormore triple bonds and typically from 2 to about 10 carbon atoms; or inanother embodiment, from 2 to about 8 carbon atoms; in anotherembodiment, from 2 to about 6 carbon atoms; and in another embodiment,from 2 to about 4 carbon atoms. Examples of such substituents includeethynyl, 2-propynyl, 3-propynyl, 2-butynyl and 3-butynyl and the like.

The term “carbocyclyl” (alone or in combination with another term(s))means a saturated cyclic (i.e., “cycloalkyl”), partially saturatedcyclic (i.e., “cycloalkenyl”), or completely unsaturated (i.e., “aryl”)hydrocarbyl substituent containing from 3 to 14 carbon ring atoms (“ringatoms” are the atoms bound together to form the ring or rings of acyclic substituent). A carbocyclyl may be a single-ring (monocyclic) orpolycyclic ring structure.

A carbocyclyl may be a single ring structure, which typically containsfrom 3 to 8 ring atoms, more typically from 3 to 6 ring atoms, and evenmore typically 5 to 6 ring atoms. Examples of such single-ringcarbocyclyls include cyclopropyl (cyclopropanyl), cyclobutyl(cyclobutanyl), cyclopentyl (cyclopentanyl), cyclopentenyl,cyclopentadienyl, cyclohexyl (cyclohexanyl), cyclohexenyl,cyclohexadienyl, cyclooxtanyl, and phenyl. A carbocyclyl mayalternatively be polycyclic (i.e., may contain more than one ring).Examples of polycyclic carbocyclyls include bridged, fused, andspirocyclic carbocyclyls. In a spirocyclic carbocyclyl, one atom iscommon to two different rings. Examples of spirocyclic carbocyclylsinclude spiropentanyl, spiro[3.5]nonanyl, and spiro[2.5]octanyl. In abridged carbocyclyl, the rings share at least two common non-adjacentatoms. Examples of bridged carbocyclyls include bicyclo[2.2.1]heptanyl,bicyclo[2.2.1]hept-2-enyl, and adamantanyl(tricyclo[3.3.1.1^(3,7)]decanyl). In a fused-ring carbocyclyl system,two or more rings may be fused together, such that two rings share onecommon bond. Examples of two- or three-fused ring carbocyclyls includenaphthalenyl, tetrahydronaphthalenyl (tetralinyl), indenyl, indanyl(dihydroindenyl), anthracenyl, phenanthrenyl, and decalinyl.

The term “cycloalkyl” (alone or in combination with another term(s))means a saturated cyclic hydrocarbyl substituent containing from 3 to 14carbon ring atoms. A cycloalkyl may be a single carbon ring, whichtypically contains from 3 to 8 carbon ring atoms and more typically from3 to 6 ring atoms. Examples of single-ring cycloalkyls includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, andcyclooctanyl. A cycloalkyl may alternatively be polycyclic or containmore than one ring. Examples of polycyclic cycloalkyls include bridged,fused, and spirocyclic carbocyclyls. Examples of bridged cycloalkylsinclude adamantanyl(tricyclo[3.3.1.1^(3,7)]decanyl), andbicyclo[3.1.1]heptanyl.

The term “C_(x)-C_(y) cycloalkyl” means a cycloalkyl ring systemcontaining from x to y carbon atoms. For example “C₃-C₇ cycloalkyl”means a cycloalkyl ring system containing from 3 to 7 carbon atoms.

The term “cycloalkenyl” (alone or in combination with another term(s))means a partially saturated cyclic hydrocarbyl substituent containingfrom 3 to 14 carbon ring atoms. A cycloalkenyl may be a single carbonring, which typically contains from 3 to 8 carbon ring atoms and moretypically from 4 to 6 ring atoms. Examples of single-ring cycloalkenylsinclude cyclopentenyl, and cyclohexenyl. A cycloalkenyl mayalternatively be polycyclic or contain more than one ring. Examples ofpolycyclic cycloalkenyls include bridged, fused, and spirocycliccarbocyclyls. Examples of bridged cycloalkenyls includebicyclo[2.2.1]hept-2-enyl.

The term “C_(x)-C_(y) cycloalkenyl” means a cycloalkenyl ring systemcontaining from x to y carbon atoms. For example “C₄-C₇ cycloalkenyl”means a cycloalkenyl ring system containing from 4 to 7 carbon atoms.

The term “aryl” (alone or in combination with another term(s)) means anaromatic carbocyclyl containing from 6 to 14 carbon ring atoms. An arylmay be monocyclic or polycyclic (i.e., may contain more than one ring).In the case of polycyclic aromatic rings, only one ring the polycyclicsystem is required to be unsaturated while the remaining ring(s) may besaturated, partially saturated or unsaturated. Examples of aryls includephenyl, naphthalenyl, indenyl, indanyl, and tetrahydronaphthyl.

The term “heteroarylene” means a divalent heteroarene.

The term “arylene” means a divalent arene.

The term “phenylene” means a divalent benzene.

In some instances, the number of carbon atoms in a substituent (e.g.,alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, and aryl)is indicated by the prefix “C_(x)-C_(y)-”, wherein x is the minimum andy is the maximum number of carbon atoms. Thus, for example,“C₁-C₆-alkyl” refers to an alkyl containing from 1 to 6 carbon atoms.Illustrating further, “C₃-C₈-cycloalkyl” means a saturated hydrocarbylring containing from 3 to 8 carbon ring atoms.

The term “C_(x-y) branched chain alkyl” means a saturated hydrocarbylsubstituent containing from x to y carbons wherein attachment occursthrough a dialkyl trivalent- or trialkyl tetravalent-carbon radical.Examples of such substituents include isopentanyl (pentan-3-yl),neopentanyl(2,2-dimethylpropan-2-yl), heptan-4-yl, and2,6-dimethylheptan-4-yl.

The term, “C₃₋₁₁ branched chain alkyl” means a saturated hydrocarbylsubstituent containing from 3 to 11 carbons wherein attachment occursthrough a dialkyl trivalent- or trialkyl tetravalent-carbon radical.

The term “hydrogen” (alone or in combination with another term(s)) meansa hydrogen radical, and may be depicted as —H.

The term “hydroxy” (alone or in combination with another term(s)) means—OH.

The term “carboxy” (alone or in combination with another term(s)) means—C(O)—OH.

The term “amino” (alone or in combination with another term(s)) means—NH₂.

The term “halogen” or “halo” (alone or in combination with anotherterm(s)) means a fluorine radical (which may be depicted as —F),chlorine radical (which may be depicted as —Cl), bromine radical (whichmay be depicted as —Br), or iodine radical (which may be depicted as—I).

If a substituent is described as being “substituted”, a non-hydrogenradical is in the place of hydrogen radical on a carbon or nitrogen ofthe substituent. Thus, for example, a substituted alkyl substituent isan alkyl substituent in which at least one non-hydrogen radical is inthe place of a hydrogen radical on the alkyl substituent. To illustrate,monofluoroalkyl is alkyl substituted with a fluoro radical, anddifluoroalkyl is alkyl substituted with two fluoro radicals. It shouldbe recognized that if there are more than one substitution on asubstituent, each non-hydrogen radical may be identical or different(unless otherwise stated).

If a substituent is described as being “optionally substituted”, thesubstituent may be either (1) not substituted or (2) substituted. If asubstituent is described as being optionally substituted with up to aparticular number of non-hydrogen radicals, that substituent may beeither (1) not substituted; or (2) substituted by up to that particularnumber of non-hydrogen radicals or by up to the maximum number ofsubstitutable positions on the substituent, whichever is less. Thus, forexample, if a substituent is described as a heteroaryl optionallysubstituted with up to 3 non-hydrogen radicals, then any heteroaryl withless than 3 substitutable positions would be optionally substituted byup to only as many non-hydrogen radicals as the heteroaryl hassubstitutable positions. To illustrate, tetrazolyl (which has only onesubstitutable position) would be optionally substituted with up to onenon-hydrogen radical. To illustrate further, if an amino nitrogen isdescribed as being optionally substituted with up to 2 non-hydrogenradicals, then a primary amino nitrogen will be optionally substitutedwith up to 2 non-hydrogen radicals, whereas a secondary amino nitrogenwill be optionally substituted with up to only 1 non-hydrogen radical.

This patent application uses the terms “substituent” and “radical”interchangeably.

The prefix “halo” indicates that the substituent to which the prefix isattached is substituted with one or more independently selected halogenradicals. For example, haloalkyl means an alkyl substituent in which atleast one hydrogen radical is replaced with a halogen radical. Examplesof haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl,difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogenradical, those halogen radicals may be identical or different (unlessotherwise stated).

The prefix “perhalo” indicates that every hydrogen radical on thesubstituent to which the prefix is attached is replaced withindependently selected halogen radicals, i.e., each hydrogen radical onthe substituent is replaced with a halogen radical. If all the halogenradicals are identical, the prefix typically will identify the halogenradical. Thus, for example, the term “perfluoro” means that everyhydrogen radical on the substituent to which the prefix is attached issubstituted with a fluorine radical. To illustrate, the term“perfluoroalkyl” means an alkyl substituent wherein a fluorine radicalis in the place of each hydrogen radical.

The term “carbonyl” (alone or in combination with another term(s)) means—C(O)—.

The term “aminocarbonyl” (alone or in combination with another term(s))means —C(O)—NH₂.

The term “oxo” (alone or in combination with another term(s)) means(═O).

The term “oxy” (alone or in combination with another term(s)) means anether substituent, and may be depicted as —O—.

The term “hydroxyalkyl” (alone or in combination with another term(s))means -alkyl-OH.

The term “alkylamino” (alone or in combination with another term(s))means -alkyl-NH₂.

The term “alkyloxy” (alone or in combination with another term(s)) meansan alkylether substituent, i.e., —O-alkyl. Examples of such asubstituent include methoxy (—O—CH₃), ethoxy, n-propoxy, isopropoxy,n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.

The term “alkylcarbonyl” (alone or in combination with another term(s))means —C(O)-alkyl.

The term “aminoalkylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-alkyl-NH₂.

The term “alkyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-alkyl.

The term “carbocyclylcarbonyl” (alone or in combination with anotherterm(s)) means —C(O)-carbocyclyl.

Similarly, the term “heterocyclylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-heterocyclyl.

The term “carbocyclylalkylcarbonyl” (alone or in combination withanother term(s)) means —C(O)-alkyl-carbocyclyl.

Similarly, the term “heterocyclylalkylcarbonyl” (alone or in combinationwith another term(s)) means —C(O)-alkyl-heterocyclyl.

The term “carbocyclyloxycarbonyl” (alone or in combination with anotherterm(s)) means —C(O)—O-carbocyclyl.

The term “carbocyclylalkyloxycarbonyl” (alone or in combination withanother term(s)) means —C(O)—O-alkyl-carbocyclyl.

The term “thio” or “thia” (alone or in combination with another term(s))means replacement by a sulfur radical, i.e. a thiaether substituentmeans an ether substituent wherein a divalent sulfur atom is in theplace of the ether oxygen atom. Such a substituent may be depicted as—S—. For example, “alkyl-thio-alkyl” means alkyl-S-alkyl(alkyl-sulfanyl-alkyl).

The term “thiol” or “sulfhydryl” (alone or in combination with anotherterm(s)) means a sulfhydryl substituent, and may be depicted as —SH.

The term “(thiocarbonyl)” (alone or in combination with another term(s))means a carbonyl wherein the oxygen atom has been replaced with asulfur. Such a substituent may be depicted as —C(S)—.

The term “sulfonyl” (alone or in combination with another term(s)) means—S(O)₂—.

The term “aminosulfonyl” (alone or in combination with another term(s))means —S(O)₂—NH₂.

The term “sulfinyl” or “sulfoxido” (alone or in combination with anotherterm(s)) means —S(O)—.

The term “heterocyclyl” (alone or in combination with another term(s))means a saturated (i.e., “heterocycloalkyl”), partially saturated (i.e.,“heterocycloalkenyl”), or completely unsaturated (i.e., “heteroaryl”)ring structure containing a total of 3 to 14 ring atoms. At least one ofthe ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), withthe remaining ring atoms being independently selected from the groupconsisting of carbon, oxygen, nitrogen, and sulfur. A heterocyclyl maybe a single-ring (monocyclic) or polycyclic ring structure.

A heterocyclyl may be a single ring, which typically contains from 3 to7 ring atoms, more typically from 3 to 6 ring atoms, and even moretypically 5 to 6 ring atoms. Examples of single-ring heterocyclylsinclude furanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl,thiophenyl (thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl,imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl,tetrazolyl, oxazolyl, oxazolidinyl, isoxazolidinyl, isoxazolyl,thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl,isothiazolidinyl, thiodiazolyl, oxadiazolyl (including1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl,1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), 1,4-dioxanyl,dioxothiomorpholinyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl,dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl),piperidinyl, diazinyl (including pyridazinyl (1,2-diazinyl), pyrimidinyl(1,3-diazinyl), or pyrazinyl (1,4-diazinyl)), piperazinyl, triazinyl(including 1,3,5-triazinyl, 1,2,4-triazinyl, and 1,2,3-triazinyl)),oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl, or 1,4-oxazinyl)),oxathiazinyl (including 1,2,3-oxathiazinyl, 1,2,4-oxathiazinyl,1,2,5-oxathiazinyl, or 1,2,6-oxathiazinyl)), oxadiazinyl (including1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or1,3,5-oxadiazinyl)), morpholinyl, azepinyl, oxepinyl, thiepinyl,diazepinyl, pyridonyl (including pyrid-2(1H)-onyl and pyrid-4(1H)-onyl),furan-2(5H)-onyl, pyrimidinyl (including pyramid-2(1H)-onyl andpyramid-4(3H)-onyl), oxazol-2(3H)-onyl, 1H-imidazol-2(3H)-onyl,pyridazin-3(2H)-onyl, and pyrazin-2(1H)-onyl.

A heterocyclyl may alternatively be polycyclic (i.e., may contain morethan one ring). Examples of polycyclic heterocyclyls include bridged,fused, and spirocyclic heterocyclyls. In a spirocyclic heterocyclyl, oneatom is common to two different rings. In a bridged heterocyclyl, therings share at least two common non-adjacent atoms. Examples of bridgedheterocyclyls include 2-oxatricyclo[3.3.1.1^(3,7)]decane. In afused-ring heterocyclyl, two or more rings may be fused together, suchthat two rings share one common bond. Examples of fused ringheterocyclyls containing two or three rings include imidazopyrazinyl(including imidazo[1,2-a]pyrazinyl), imidazopyridinyl (includingimidazo[1,2-a]pyridinyl), imidazopyridazinyl (includingimidazo[1,2-b]pyridazinyl), thiazolopyridinyl (includingthiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl), indolizinyl,pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl,pyridopyridinyl (including pyrido[3,4-b]-pyridinyl,pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl.Other examples of fused-ring heterocyclyls include benzo-fusedheterocyclyls, such as dihydrochromenyl, tetrahydroisoquinolinyl,indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl), indoleninyl(pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (includingquinolinyl (1-benzazinyl) or isoquinolinyl (2-benzazinyl)),phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (includingcinnolinyl (1,2-benzxodiazinyl) or quinazolinyl (1,3-benzodiazinyl)),benzopyranyl (including chromanyl or isochromanyl), benzoxazinyl(including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl,or 3,1,4-benzoxazinyl), benzo[d]thiazolyl, and benzisoxazinyl (including1,2-benzisoxazinyl or 1,4-benzisoxazinyl).

The term “heterocycloalkyl” (alone or in combination with anotherterm(s)) means a saturated heterocyclyl.

The term “C_(x)-C_(y) heterocycloalkyl” means a heterocycloalkyl ringsystem containing from x to y ring atoms. For example “C₃-C₇heterocycloalkyl” means a heterocycloalkyl ring system containing 3 to 7ring atoms.

The term “heterocycloalkenyl” (alone or in combination with anotherterm(s)) means a partially saturated heterocyclyl.

The term “C_(x)-C_(y) heterocycloalkenyl” means a heterocycloalkenylring system containing from x to y ring atoms. For example “C₃-C₇heterocycloalkenyl” means a heterocycloalkenyl ring system containingfrom 3 to 7 ring atoms.

The term “heteroaryl” (alone or in combination with another term(s))means an aromatic heterocyclyl containing from 5 to 14 ring atoms. Aheteroaryl may be a single ring or 2 or 3 fused rings. Examples ofheteroaryls include 6-membered ring substituents such as pyridyl,pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or1,2,3-triazinyl; 5-membered ring substituents such as triazolyl,pyrrolyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl andisothiazolyl: 6/5-membered fused ring substituents such asimidazopyrazinyl (including imidazo[1,2-a]pyrazinyl)imidazopyridinyl(including imidazo[1,2-a]pyridinyl), imidazopyridazinyl (includingimidazo[1,2-b]pyridazinyl), thiazolopyridinyl (includingthiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl),benzo[d]thiazolyl, benzothiofuranyl, benzisoxazolyl, benzoxazolyl,purinyl, and anthranilyl; and 6/6-membered fused rings such asbenzopyranyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, andbenzoxazinyl. Heteroaryls may also be heterocyles having aromatic (4N+2pi electron) resonance contributors such as pyridonyl (includingpyrid-2(1H)-onyl and pyrid-4(1H)-onyl), pyrimidonyl (includingpyramid-2(1H)-onyl and pyramid-4(3H)-onyl), pyridazin-3(2H)-onyl andpyrazin-2(1H)-onyl.

The term “C_(x)-C_(y) heteroaryl” means a heteroaryl ring systemcontaining from x to y ring atoms. For example “C₅-C₆ heteroaryl” meansa heteroaryl ring system containing from 5 to 6 ring atoms.

The term “heteroarylene” means a divalent heteroaryl group.

A prefix attached to a multi-component substituent only applies to thefirst component. To illustrate, the term “alkylcycloalkyl” contains twocomponents: alkyl and cycloalkyl. Thus, the C₁-C₆-prefix onC₁-C₆-alkylcycloalkyl means that the alkyl component of thealkylcycloalkyl contains from 1 to 6 carbon atoms; the C₁-C₆-prefix doesnot describe the cycloalkyl component. To illustrate further, the prefix“halo” on haloalkyloxyalkyl indicates that only the alkyloxy componentof the alkyloxyalkyl substituent is substituted with one or more halogenradicals. If halogen substitution may alternatively or additionallyoccur on the alkyl component, the substituent would instead be describedas “halogen-substituted alkyloxyalkyl” rather than “haloalkyloxyalkyl.”And finally, if the halogen substitution may only occur on the alkylcomponent, the substituent would instead be described as“alkyloxyhaloalkyl.”

The terms “treat”, “treating” and “treatment” refer to a method ofalleviating or abrogating a disease and/or its attendant symptoms.

The terms “prevent”, “preventing” and “prevention” refer to a method ofpreventing the onset of a disease and/or its attendant symptoms orbarring a subject from acquiring a disease. As used herein, “prevent”,“preventing” and “prevention” also include delaying the onset of adisease and/or its attendant symptoms and reducing a subject's risk ofacquiring a disease.

The term “therapeutically effective amount” refers to that amount of thecompound being administered sufficient to prevent development of oralleviate to some extent one or more of the symptoms of the condition ordisorder being treated.

The term “modulate” refers to the ability of a compound to increase ordecrease the function, or activity, of a kinase. “Modulation”, as usedherein in its various forms, is intended to encompass antagonism,agonism, partial antagonism and/or partial agonism of the activityassociated with kinase. Kinase inhibitors are compounds that, e.g., bindto, partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. Kinase activators are compounds that, e.g., bind to,stimulate, increase, open, activate, facilitate, enhance activation,sensitize or up regulate signal transduction.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The “subject” is defined herein to include animals such as mammals,including, but not limited to, primates (e.g., humans), cows, sheep,goats, horses, dogs, cats, rabbits, rats, mice and the like. Inpreferred embodiments, the subject is a human.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonmyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl (phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are sometimes designated as being of cis or transconfiguration.

Compounds of this invention may contain asymmetrically substitutedcarbon atoms in the R or S configuration, in which the terms “R” and “S”are as defined by the IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry. Pure Appl. Chem. (1976) 45, 13-10.Compounds having asymmetrically substituted carbon atoms with equalamounts of R and S configurations are racemic at those carbon atoms.Atoms with an excess of one configuration over the other are assignedthe configuration present in the higher amount, preferably an excess ofabout 85%-90%, more preferably an excess of about 95%-99%, and stillmore preferably an excess greater than about 99%. Accordingly, thisinvention includes racemic mixtures, relative and absolutestereoisomers, and mixtures of relative and absolute stereoisomers.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²p, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFat, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (200(3); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-xL inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal. Advances in Drug Research Vol. 14, pp. 2-36, Academic press, London,1985; Kato et al., J. Labelled Comp. Radiopharmaceut., 36(10):927-932(1995); Kushner et al., Can. J. Physiol. Pharmacol., 77, 79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-xL activity. Increasing theamount of an isotope present in a compound above its natural abundanceis called enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J. Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmacokinetic profile or efficacy relative to the non-isotopiccompound.

Suitable groups for X, Y¹, L¹, Y², Z¹, R¹, R², R³, m, n, and p incompounds of Formula (I) are independently selected. The describedembodiments of the present invention may be combined. Such combinationis contemplated and within the scope of the present invention. Forexample, it is contemplated that embodiments for any of X, Y¹, L¹, Y²,Z¹, R¹, R², R³, m, n, and p can be combined with embodiments defined forany other of X, Y¹, L¹, Y², Z¹, R¹, R², R³, m, n, and p.

One embodiment of this invention, therefore, pertains to compounds orand therapeutically acceptable salts thereof, metabolites, prodrugs,salts of metabolites, and salts of prodrugs thereof, which are useful asinhibitors of anti-apoptotic Bcl-xL proteins, the compounds havingFormula (I)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

Y¹ is phenylene, or C₅₋₆ heteroarylene; optionally fused to one or tworings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein Y¹ is optionally substituted with one, two,three, or four substituents independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁷R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸. OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₂₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵S, S(O)R¹⁵, SO₂R¹⁵,C(O)R¹⁵, CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁴),C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶. SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₄ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6; and

p is 0, 1, or 2.

In one embodiment of Formula (I), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (I), nis 0 or 1. In another embodiment of Formula (I), n is 0 or 1; and eachR² is independently deuterium or C₁₋₆ alkyl. In another embodiment ofFormula (I), m, n, and p are 0.

In one embodiment of Formula (I), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (I), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (I), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (I), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (I), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (I), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (I), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (I), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(I), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (I), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (I), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (I), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (I). X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (I). X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (I), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (I), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (I), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (I), Z¹ is

In another embodiment of Formula (I), Z¹ is

In another embodiment of Formula (I), Z¹ is

In one embodiment of Formula (I), Y¹ is phenylene, or C₅₋₆heteroarylene; optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene. C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY¹ is optionally substituted with one, two, three, or four substituentsindependently selected from the group consisting of R⁵, OR⁵SR⁵S(O)R⁵,SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵,NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂,NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵,C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂,SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₃, NO₂. F, Cl, Br and I. Inanother embodiment of Formula (I), Y¹ is phenylene or C₅₋₆heteroarylene; optionally fused to one or two rings selected from thegroup consisting of C₅₋₆ heteroarene and C₃₋₈ heterocycloalkane; whereinY¹ is optionally substituted with one or two substituents independentlyselected from the group consisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Brand I. In another embodiment of Formula (I), Y¹ is pyrrolyl, pyrazolyl,triazolyl, pyridinyl, or phenyl. In another embodiment of Formula (I),Y¹ is pyrrolyl, pyrazolyl, or triazolyl. In another embodiment ofFormula (I), Y¹ is pyridinyl or phenyl. In another embodiment of Formula(I), Y¹ is pyrrolyl. In another embodiment of Formula (I), Y¹ ispyrazolyl. In another embodiment of Formula (I), Y¹ is triazolyl. Inanother embodiment of Formula (I), Y¹ is pyridinyl. In anotherembodiment of Formula (I), Y¹ is phenyl. In another embodiment ofFormula (I), Y¹ is pyrrolyl, pyrazolyl, triazolyl, pyridinyl, or phenyl;wherein the pyrrolyl, pyrazolyl, triazolyl, pyridinyl, and phenylrepresented by Y¹ are optionally substituted with one, or twosubstituents independently selected from the group consisting of R⁵,CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I.

In one embodiment of Formula (I), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇,cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₇ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (I), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸)₂,C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (I), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (I), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is 0 or1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In one embodiment of Formula (I), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

Y¹ is phenylene or C₅₋₆ heteroarylene; optionally fused to one ringselected from the group consisting of C₅₋₆ heteroarene and C₃₋₈heterocycloalkane; wherein Y¹ is optionally substituted with one or twosubstituents independently selected from the group consisting of R⁵,CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸)₂, C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring,wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₄ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₆ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₆ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1; and

p is 0.

Still another embodiment pertains to a compound having Formula (I)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{4-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(5,6-difluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(benzyloxy)benzyl]-1H-pyrazol-1-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(7-chloro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-cyano-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-carboxy-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,4-dihydro)-2H-chromen-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-{[3-(dimethylamino)propyl]amino}-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)propoxy]benzyl)-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(pyridin-4-yl-methoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)prop-1-yn-1-yl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-phenylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4,4-difluoro)cyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzo    thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(diphenylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(morpholin-4-yl)-1-phenylpropyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[3-(morpholin-4-yl)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzo    thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methylpropyl)cyclohexyl]methyl}-1H-pyrazol)-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(2-methoxyethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,3-dimethylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(1,4-dioxan-2-ylmethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methyphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-carboxy-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(piperidin-1-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6,6′-bis[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3′-bipyridine-2,2′-dicarboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(methoxymethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,3-dimethyl-1-(morpholin-4-yl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[1-cyclohexyl-3-(morpholin-4-yl)propyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-5-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[3-(morpholin-4-yl)propoxy]cycloheptyl}-methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,33-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxycyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({1-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano)-2-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-hydroxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dimethoxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(1,4-dioxan-2-ylmethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(morpholin-4-yl)-2-oxoethoxy]cyclohexyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dihydroxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(dimethylamino)cyclohexyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-{3,3-dimethyl-1-[2-(methylamino)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(II)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, n, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, or 3.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (II)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, or 3; and

p is 0, 1, or 2.

In one embodiment of Formula (II), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (II),n is 0 or 1. In another embodiment of Formula (II), n is 0 or 1; andeach R² is independently deuterium or C₁₋₆ alkyl. In another embodimentof Formula (II), m, n, and p are 0.

In one embodiment of Formula (II), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (II), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (II). X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (II), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (II), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (II), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (II), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (II), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(II), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (II), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (II), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (II), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (II), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (II), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (II), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹¹S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (II), Z¹ is

In another embodiment of Formula (II), Z¹ is

In another embodiment of Formula (II), Z¹ is

In one embodiment of Formula (II), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (II), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸),C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (II), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (II), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is 0 or 1;R^(6A) is independently selected from the group consisting of hydrogen,and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, are hydrogen.

In one embodiment of Formula (II), o is 0. In another embodiment ofFormula (II), o is 2. In another embodiment of Formula (II), o is 0, 1,2, or 3. In another embodiment of Formula (II), o is 1, 2, or 3; andR^(x), at each occurrence, is independently selected from the groupconsisting of, R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I. In another embodiment of Formula (II),o is 1, 2, or 3; and R^(x), at each occurrence, is independentlyselected from the group consisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Brand I. In another embodiment of Formula (II), o is 1 or 2; R^(x), ateach occurrence, is independently selected from the group consisting ofR⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I; and R⁵, at each occurrence, isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, and cycloalkyl. Inanother embodiment of Formula (II), o is 1 or 2; R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CN, F, Cl, Br and I; and R⁵, at each occurrence, is independentlyselected from the group consisting of C₁₋₂ alkyl, and C₁ haloalkyl. Inanother embodiment of Formula (II), o is 1 or 2; R^(x) is R⁵ or CN; andR⁵ is CH₃. In another embodiment of Formula (II), o is 1; and R^(x) isCN.

In one embodiment of Formula (II), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸)₂, C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring;wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₄ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₄ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵ C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1;

o is 0, 1, 2, or 3; and

p is 0.

Still another embodiment pertains to a compound having Formula (II)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-carboxy-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(piperidin-1-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylic    acid;

6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylicacid;

-   N-(1,3-benzothiazol-2-yl)-2-yl)-2-{5-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(dimethylamino)cyclohexyl]methyl)-2-methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylic    acid-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(III)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, or 2.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (III)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)ORS, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇, heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, or 2; and

p is 0, 1, or 2.

In one embodiment of Formula (III), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (III),n is 0 or 1. In another embodiment of Formula (III), n is 0 or 1; andeach R² is independently deuterium or C₁₋₆ alkyl. In another embodimentof Formula (III), m, n, and p are 0.

In one embodiment of Formula (III), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (III), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (III), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (III), X is heteroaryl, whichis substituted with two R⁴. In another embodiment of Formula (III), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (III), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (III), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (III), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(III), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (III), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (III), X is benzo[d]thiazolyl, which issubstituted with two R⁴. In another embodiment of Formula (III), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (III), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (III), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (III), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹⁰, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹¹C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (III), Z¹ is

In another embodiment of Formula (III), Z¹ is

In another embodiment of Formula (III), Z¹ is

In one embodiment of Formula (III), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃, NO₂,F, Cl, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₇cycloalkene, benzene, C₅₋₈ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (III), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸)₂,C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (III), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (III), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is 0 or 1;R^(6A) is independently selected from the group consisting of hydrogen,and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, are hydrogen.

In one embodiment of Formula (III), o is 0. In another embodiment ofFormula (III), o is 2. In another embodiment of Formula (III), o is 0,1, or 2. In another embodiment of Formula (III), o is 1 or 2; and R^(x),at each occurrence, is independently selected from the group consistingof, R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵,NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I. In another embodiment of Formula(III), o is 1 or 2; and R^(x), at each occurrence, is independentlyselected from the group consisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Brand I. In another embodiment of Formula (III), o is 1 or 2; R^(x), ateach occurrence, is independently selected from the group consisting ofR⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I; and R⁵, at each occurrence, isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, and cycloalkyl. Inanother embodiment of Formula (III), o is 1 or 2; R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CN, F, Cl, Br and I; and R⁵, at each occurrence, is independentlyselected from the group consisting of C₁₋₂ alkyl, and C₁ haloalkyl. Inanother embodiment of Formula (III), o is 1 or 2; R^(x) is R⁵ or CN; andR⁵ is CH₃. In another embodiment of Formula (III), o is 1; and R^(x) isCN.

In one embodiment of Formula (III), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C_(L)7 cycloalkyl, C₃₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸)₂, C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring;wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹³, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₆ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₆ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1;

o is 0, 1, or 2; and

p is 0.

Still another embodiment pertains to a compound having Formula (III)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{4-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(5,6-difluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydro)isoquinolin-2(1H)-yl]-3-[1-(3-methylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(7-chloro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-cyano-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxyl    is acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(benzyloxy)benzyl]-1H-pyrazol-1-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-carboxy-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,4-dihydro-2H-chromen-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-{[3-(dimethylamino)propyl]amino}-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-([1-(4-{[3-(dimethylamino)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(pyridin-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)prop-1-yn-1-yl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-nitrobenzol)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-phenylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4,4-difluorcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(trifluormethyl)cyclohexyl]methyl}-1-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(diphenylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-morpholin-4-yl)-1-phenylpropyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiaol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[3-(morpholin-4-yl)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methylpropyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(2-methoxyethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,3-dimethylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(1,4-dioxan-2-ylmethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(methoxymethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,3-dimethyl-1-(morpholin-4-yl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   N-1,3-benzothiazol-2-yl)-2-{5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[1-cyclohexyl-3-(morpholin-4-yl)propyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[3-(morpholin-4-yl)propoxy]cycloheptyl)methyl}-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid,-   N-(1,3-benzothiazol-2-yl)-2-(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl)-1,2,3,4-perhydroisoquinoline-8-carboxamide;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxycyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({1-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-hydroxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dimethoxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(1,4-dioxan-2-ylmethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(morpholin-4-yl)-2-oxoethoxy]cyclohexyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dihydroxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-{3,3-dimethyl-1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1({3,3-dimethyl-1-[2-(methylamino)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(IV)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R′ is asdescribed herein for substituents on Y¹, and o is 0 or 1.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (IV)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x) is independently selected from the group consisting of R⁵, OR⁵,SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵,N(R⁵), NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₁, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)₄CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸), C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵ is independently selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl,heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶. SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0 or 1; and

p is 0, 1, or 2.

In one embodiment of Formula (IV), in is 0, 1, 2, or 3; n is 0.1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (IV),n is 0 or 1. In another embodiment of Formula (IV), n is 0 or 1; andeach R² is independently deuterium or C₁₋₆ alkyl. In another embodimentof Formula (IV), m, n, and p are 0.

In one embodiment of Formula (IV), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (IV), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (IV), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (IV), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (IV), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (IV), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(IV). X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (IV), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (IV), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (IV), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (IV), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (IV), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (IV), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹⁰)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (IV), Z¹ is

In another embodiment of Formula (IV), Z¹ is

In another embodiment of Formula (IV), Z¹ is

In one embodiment of Formula (IV), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₇ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO_(z)R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (IV), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁷R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸),C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (IV), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (IV), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is 0 or 1;R^(6A) is independently selected from the group consisting of hydrogen,and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, are hydrogen.

In one embodiment of Formula (IV), o is 0. In another embodiment ofFormula (IV), is I. In another embodiment of Formula (IV), o is 0 or 1.In another embodiment of Formula (IV), o is 1; and R^(x) isindependently selected from the group consisting of, R⁵, OR⁵, SR⁵,S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂,NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵, NR⁵C(O)OR⁵,NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵, NR⁵C(O)N(R⁵)₂,C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵, C(O)NHSO₂R⁵,C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I. In another embodiment of Formula (IV), o is 1; andR^(x) is independently selected from the group consisting of R⁵,CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I. In another embodiment of Formula(IV), o is 1; R⁵, at each occurrence, is independently selected from thegroup consisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I; and R⁵ isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, and cycloalkyl. Inanother embodiment of Formula (IV), o is 1; R^(x) is independentlyselected from the group consisting of R⁵, CN, F, Cl, Br and I; and R⁵,at each occurrence, is independently selected from the group consistingof C₁₋₂ alkyl, and C₁ haloalkyl. In another embodiment of Formula (IV),o is 1; R^(x) is R⁵ or CN; and R⁵ is CH₃. In another embodiment ofFormula (IV), o is 1; and R^(x) is CN. In another embodiment of Formula(IV), o is 1; R^(x) is R⁵; and R⁵ is CH₃.

In one embodiment of Formula (IV), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), and (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷) and

Y² is selected from the group consisting of C₃₋₁₁, branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇, cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸)₂, C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring;wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₆ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₆ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1;

o is 0 or 1; and

p is 0.

Still another embodiment pertains to a compound having Formula (IV)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}pyridine-2-carboxylic    acid, and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(V)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, 3, or 4.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (V)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸), CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R¹⁰,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)₂R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹³, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶, SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R¹⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR¹⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R¹⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, 3, or 4; and

p is 0, 1, or 2.

In one embodiment of Formula (V), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (V), nis 0 or 1. In another embodiment of Formula (V), n is 0 or 1; and eachR² is independently deuterium or C₁₋₆ alkyl. In another embodiment ofFormula (V), m, n, and p are 0.

In one embodiment of Formula (V), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (V), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (V), X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (V), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (V), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR¹² or halogen.In another embodiment of Formula (V), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (V), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (V), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(V), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴ and each R⁴is independently F.

In one embodiment of Formula (V), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (V), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (V), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (V), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (V), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (V), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)R¹¹,NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (V). Z¹ is

In another embodiment of Formula (V), Z¹ is

In another embodiment of Formula (V), Z¹ is

In one embodiment of Formula (V), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (V), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸),C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (V), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (V), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is0 or 1; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R^(6A) at each occurrence, arehydrogen.

In one embodiment of Formula (V), o is 0. In another embodiment ofFormula (V), o is 1. In another embodiment of Formula (V), o is 0 or 1.In another embodiment of Formula (V), o is 0, 1, 2, 3, or 4. In anotherembodiment of Formula (V), o is 0, 1, 2, 3, or 4; and R^(x), at eachoccurrence, is independently selected from the group consisting of, R⁵,OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂, NHR⁵,N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I. In another embodiment of Formula (V),o is 1 or 2; and R^(x), at each occurrence, is independently selectedfrom the group consisting of R⁵CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I. Inanother embodiment of Formula (V), o is 1 or 2; R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CO(O)R⁵, CO(O)H. CN, F, Cl, Br and I; and R⁵, at each occurrence, isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, and cycloalkyl. Inanother embodiment of Formula (V), o is 1; R^(x), at each occurrence, isindependently selected from the group consisting of R⁵, CN, F, Cl, Brand I; and R⁵, at each occurrence, is independently selected from thegroup consisting of C₁₋₂ alkyl, and C₁ haloalkyl. In another embodimentof Formula (V), o is 1 or 2; R^(x) is R⁵ or CN; and R⁵ is CH₃. Inanother embodiment of Formula (V), o is 1; and R^(x) is CN. In anotherembodiment of Formula (V), o is 1; and R^(x) is CH₃.

In one embodiment of Formula (V), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸), C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring;wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₆ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₆ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₆ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1;

o is 0, 1, 2, 3, or 4; and

p is 0.

Still another embodiment pertains to a compound having Formula (V)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridin-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.

In another aspect, the present invention provides compounds of Formula(VI)

and therapeutically acceptable salts, metabolites, prodrugs, salts ofmetabolites, and salts of prodrugs thereof, wherein X, L¹, Y², Z¹, R¹,R², R³, m, n, and p are as described herein for Formula (I); R^(x) is asdescribed herein for substituents on Y¹, and o is 0, 1, 2, or 3.

One embodiment of this invention pertains to compounds ortherapeutically acceptable salts thereof, which are useful as inhibitorsof anti-apoptotic Bcl-xL proteins, the compounds having Formula (VI)

wherein

X is heteroaryl; wherein the heteroaryl represented by X is optionallysubstituted with one, two, three, or four R⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵,OC(O)OR⁵, NH₂, NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵,NHC(O)OR⁵, NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one or two rings selected from thegroup consisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereinY² is optionally substituted with one, two, three, four, or fivesubstituents independently selected from the group consisting of R⁸,OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸,N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸,NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸,NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸,C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄, cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl representedby Y² are optionally fused to one or two rings selected from the groupconsisting of C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈ heterocycloalkene; whereineach Y² and each ring fused to Y² are optionally substituted with one,two, three, four, or five substituents independently selected from thegroup consisting of R⁸, OR⁸, SR⁸, S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸,OC(O)R⁸. OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂, NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸,NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸, NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂,NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂, C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH,C(O)NHOR⁸, C(O)NHSO₂R⁸, C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂,CO(O)H, C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I;

Z¹ is selected from the group consisting of C(O)OR⁹, C(O)NR¹⁰R¹¹,C(O)R¹¹, NR¹⁰C(O)R¹¹, NR¹⁰C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹,C(═NOR¹⁰)NR¹⁰R¹¹, NR¹⁰C(═NCN)NR¹⁰R¹¹, NR¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹,S(O)₂NR¹⁰R¹¹, N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹⁰,C(═NR¹⁰)NR¹⁰R¹¹, halogen, NO₂, and CN; or

Z¹ is selected from the group consisting of

R¹, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R², at each occurrence, is independently selected from the groupconsisting of deuterium, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

two R² that are attached to the same carbon atom, together with saidcarbon atom, optionally form a ring selected from the group consistingof heterocycloalkyl, heterocycloalkenyl, cycloalkyl, and cycloalkenyl;

R³, at each occurrence, is independently selected from the groupconsisting of halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of NR¹²R¹³, OR¹², CN, NO₂, halogen, C(O)OR¹², C(O)NR¹²R¹³,NR¹²C(O)R¹³, NR¹²S(O)₂R¹⁴, NR¹²S(O)R¹⁴, S(O)₂R¹⁴, S(O)R¹⁴ and R¹⁴;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;

R^(6A) is independently selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, OR¹⁵, SR¹⁵, S(O)R¹⁵, SO₂R¹⁵, C(O)R¹⁵,CO(O)R¹⁵, OC(O)R¹⁵, OC(O)OR¹⁵, NH₂, NHR¹⁵, N(R¹⁵)₂, NHC(O)R¹⁵,NR¹⁵C(O)R¹⁵, NHS(O)₂R¹⁵, NR¹⁵S(O)R¹⁵, NHC(O)OR¹⁵, NR¹⁵C(O)OR¹⁵,NHC(O)NH₂, NHC(O)NHR¹⁵, NHC(O)N(R¹⁵)₂, NR¹⁵C(O)NHR¹⁵, NR¹⁵C(O)N(R¹⁵)₂,C(O)NH₂, C(O)NHR¹⁵, C(O)N(R¹⁵)₂, C(O)NHOH, C(O)NHOR¹⁵, C(O)NHSO₂R¹⁵,C(O)NR¹⁵SO₂R¹⁵, SO₂NH₂, SO₂NHR¹⁵, SO₂N(R¹⁵)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,aryl, heterocyclyl, cycloalkyl, and cycloalkenyl; wherein the R⁸C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl are optionallysubstituted with one, two, three, four, five, or six substituentsindependently selected from the group consisting of R¹⁶, OR¹⁶. SR¹⁶,S(O)R¹⁶, SO₂R¹⁶, C(O)R¹⁶, CO(O)R¹⁶, OC(O)R¹⁶, OC(O)OR¹⁶, NH₂, NHR¹⁶,N(R¹⁶)₂, NHC(O)R¹⁶, NR¹⁶C(O)R¹⁶, NHS(O)₂R⁶, NR¹⁶S(O)₂R¹⁶, NHC(O)OR¹⁶,NR¹⁶C(O)OR⁶, NHC(O)NH₂, NHC(O)NHR¹⁶, NHC(O)N(R¹⁶)₂, NR¹⁶C(O)NHR¹⁶,NR¹⁶C(O)N(R⁶)₂, C(O)NH₂, C(O)NHR¹⁶, C(O)N(R¹⁶)₂, C(O)NHOH, C(O)NHOR¹⁶,C(O)NHSO₂R¹⁶, C(O)NR¹⁶SO₂R¹⁶, SO₂NH₂, SO₂NHR¹⁶, SO₂N(R¹⁶)₂, CO(O)H,C(O)H, OH, CN, N₃, NO₂, F, Cl, Br and I; wherein the R⁸ aryl,heterocyclyl, cycloalkyl, and cycloalkenyl are optionally substitutedwith one, two, or three substituents independently selected from thegroup consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, (O), OH, CN, NO₂, OCF₃, OCF₂CF₃,F, Cl, Br and I;

R⁹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, cycloalkyl, phenyl and (CH₂)₁₋₄ phenyl;and

R¹⁰ and R¹¹, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ haloalkyl, phenyl and (CH₂)₁₋₄-phenyl; or

R¹⁰ and R¹¹, or R¹⁰ and R⁹, together with the atom to which each isattached are combined to form a heterocyclyl;

R^(k), at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇heterocycloalkyl, C₃₋₇ cycloalkyl and C₁₋₆ haloalkyl; wherein theR^(k)C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are optionallysubstituted with aryl, heterocyclyl, cycloalkyl, or cycloalkenyl;

R¹² and R¹³, at each occurrence, are each independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₂₋₄ haloalkyl and (CH₂)₁₋₄ phenyl;

R¹⁴, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ haloalkyl;

R¹² and R¹³, or R¹² and R¹⁴, at each occurrence, together with the atomto which each is attached, are optionally combined to form aheterocyclyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocyclyl, cycloalkyl, and cycloalkenyl;wherein the R¹⁵C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,and C₁₋₄ hydroxyalkyl are optionally substituted with one, two, or threesubstituents independently selected from the group consisting of C₁₋₄alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,C₁₋₄ alkoxy, aryl, heterocycloalkyl, heterocycloalkenyl, heteroaryl,cycloalkyl, and cycloalkenyl, NH₂, C(O)NH₂, SO₂NH₂, C(O)H, C(O)OH, (O),OH, CN, NO₂, OCF₃, OCF₂CF₃, F, Cl, Br and I;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl,C₁₋₄ hydroxyalkyl, aryl, heterocycloalkyl, heterocycloalkenyl,heteroaryl, cycloalkyl, and cycloalkenyl; wherein the R¹⁶C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, and C₁₋₄ hydroxyalkyl areoptionally substituted with one substituent independently selected fromthe group consisting of OCH₃, OCH₂CH₂OCH₃, and OCH₂CH₂NHCH₃;

q is 1, 2, or 3;

s is 0, 1, 2, or 3;

r is 0, 1, 2, or 3;

wherein the sum of s and r is 0, 1, or 2;

m is 0, 1, 2, or 3;

n is 0, 1, 2, 3, 4, 5, or 6;

o is 0, 1, 2, or 3; and

p is 0, 1, or 2.

In one embodiment of Formula (VI), m is 0, 1, 2, or 3; n is 0, 1, 2, 3,4, 5, or 6; and p is 0, 1, or 2. In another embodiment of Formula (VI),n is 0 or 1. In another embodiment of Formula (VI), n is 0 or 1; andeach R² is independently deuterium or C₁₋₆ alkyl. In another embodimentof Formula (VI), m, n, and p are 0.

In one embodiment of Formula (VI), X is heteroaryl, which is optionallysubstituted with one, two, three or four R⁴. In another embodiment ofFormula (VI), X is heteroaryl, which is unsubstituted. In anotherembodiment of Formula (VI). X is heteroaryl, which is substituted withone R⁴. In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with two R⁴. In another embodiment of Formula (VI), X isheteroaryl, which is substituted with one R⁴, and R⁴ is OR² or halogen.In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with two R⁴, and each R⁴ is independently OR¹² or halogen.In another embodiment of Formula (VI), X is heteroaryl, which issubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (VI), X is heteroaryl, which is substituted withtwo R⁴, and each R⁴ is independently F.

In one embodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are optionally substituted with one,two, three or four R⁴. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are unsubstituted. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with one R⁴, and R⁴ isOR¹² or halogen. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently OR¹² or halogen. In another embodiment of Formula(VI), X is benzo[d]thiazolyl, thiazolo[5,4-b]pyridinyl,thiazolo[4,5-c]pyridinyl, imidazo[1,2-a]pyridinyl,thiazolo[5,4-c]pyridinyl, thiazolo[4,5-b]pyridinyl,imidazo[1,2-a]pyrazinyl, or imidazo[1,2-b]pyridazinyl, which aresubstituted with one R⁴, and R⁴ is Cl, F, or methoxy. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl,thiazolo[5,4-b]pyridinyl, thiazolo[4,5-c]pyridinyl,imidazo[1,2-a]pyridinyl, thiazolo[5,4-c]pyridinyl,thiazolo[4,5-b]pyridinyl, imidazo[1,2-a]pyrazinyl, orimidazo[1,2-b]pyridazinyl, which are substituted with two R⁴, and eachR⁴ is independently F.

In one embodiment of Formula (VI), X is benzo[d]thiazolyl, which isoptionally substituted with one, two, three or four R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl, which isunsubstituted. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, which is substituted with one R⁴. In anotherembodiment of Formula (VI), X is benzo[d]thiazolyl, which is substitutedwith two R⁴. In another embodiment of Formula (VI), X isbenzo[d]thiazolyl, which is substituted with one R⁴, and R⁴ is OR¹² orhalogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl,which is substituted with two R⁴, and each R⁴ is independently OR¹² orhalogen. In another embodiment of Formula (VI), X is benzo[d]thiazolyl,which is substituted with one R⁴, and R⁴ is Cl, F, or methoxy. Inanother embodiment of Formula (VI), X is benzo[d]thiazolyl, which issubstituted with two R⁴, and each R⁴ is independently F.

In one embodiment of Formula (VI), Z¹ is selected from the groupconsisting of C(O)OR⁹, C(O)NR¹⁰R¹¹, C(O)R¹¹, NR¹⁰C(O)NR¹¹,NR¹¹C(O)NR¹⁰R¹¹, OC(O)NR¹⁰R¹¹, NR¹⁰C(O)OR⁹, C(═NOR¹⁰)NR¹⁰R¹¹,NR¹⁰C(═NCN)NR¹¹R¹¹, R¹⁰S(O)₂NR¹⁰R¹¹, S(O)₂R⁹, S(O)₂NR¹⁰R¹¹,N(R¹⁰)S(O)₂R¹¹, NR¹⁰C(═NR¹¹)NR¹⁰R¹¹, C(═S)NR¹⁰R¹¹, C(═NR¹⁰)NR¹⁰R¹¹,halogen, NO₂, and CN; or Z¹ is selected from the group consisting of

In another embodiment of Formula (VI), Z¹ is

In another embodiment of Formula (VI), Z¹ is

In another embodiment of Formula (VI), Z¹ is

In one embodiment of Formula (VI). L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)NR^(6A)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O—(CR⁶R⁷)_(r); and Y² is selected from the groupconsisting of C₃₋₁₁₁, branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two rings selected from the group consistingof C₃₋₈ cycloalkane, C₃₋₈ cycloalkene, benzene, C₅₋₆ heteroarene, C₃₋₈heterocycloalkane, and C₃₋₈ heterocycloalkene; wherein Y² is optionallysubstituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₂, NO,F, C, Br and I; or L¹ is a bond; and Y² is selected from the groupconsisting of C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl,and C₃₋₇ heterocyclyl represented by Y² are optionally fused to one ortwo rings selected from the group consisting of C₃₋₈ cycloalkane, C₃₋₈cycloalkene, benzene, C₁₋₆ heteroarene, C₃₋₈ heterocycloalkane, and C₃₋₈heterocycloalkene; wherein each Y² and each ring fused to Y² areoptionally substituted with one, two, three, four, or five substituentsindependently selected from the group consisting of R⁸, OR⁸, SR⁸,S(O)R⁸, SO₂R⁸, C(O)R⁸, CO(O)R⁸, OC(O)R⁸, OC(O)OR⁸, NH₂, NHR⁸, N(R⁸)₂,NHC(O)R⁸, NR⁸C(O)R⁸, NHS(O)₂R⁸, NR⁸S(O)₂R⁸, NHC(O)OR⁸, NR⁸C(O)OR⁸,NHC(O)NH₂, NHC(O)NHR⁸, NHC(O)N(R⁸)₂, NR⁸C(O)NHR⁸, NR⁸C(O)N(R⁸)₂,C(O)NH₂, C(O)NHR⁸, C(O)N(R⁸)₂, C(O)NHOH, C(O)NHOR⁸, C(O)NHSO₂R⁸,C(O)NR⁸SO₂R⁸, SO₂NH₂, SO₂NHR⁸, SO₂N(R⁸)₂, CO(O)H, C(O)H, OH, CN, N₃,NO₂, F, Cl, Br and I.

In another embodiment of Formula (VI), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and Y² is selected from thegroup consisting of C₃₋₁₁ branched chain alkyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein the C₃₋₇cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl areoptionally fused to one or two benzene rings; wherein Y² is optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R⁸, OR⁸, SO₂R⁸, CO(O)R⁸, NHR⁸, N(R⁸)₂,C(O)H, OH, CN, NO₂, F, Cl, Br and I; or L¹ is a bond; and Y² is selectedfrom the group consisting of C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇ heterocyclylrepresented by Y² are optionally fused to one benzene ring; wherein eachY² and each ring fused to Y² are optionally substituted with onesubstituent independently selected from the group consisting of R⁸,C(O)NHR⁸, F, Cl, Br and I.

In another embodiment of Formula (VI), L¹ is (CR⁶R⁷)_(q); and Y² isselected from the group consisting of C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl; wherein R⁶ and R⁷, at eachoccurrence, are R¹⁵ or hydrogen; and q is 1, 2, or 3.

In another embodiment of Formula (VI), L¹ is selected from the groupconsisting of (CR⁶R⁷)_(q), (CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)—(CR⁶R⁷)_(r),and (CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); q is 1, 2, or 3; s is 0; r is0 or i; R^(6A) is independently selected from the group consisting ofhydrogen, and C₁₋₆ alkyl; and R⁶ and R⁷, at each occurrence, arehydrogen.

In one embodiment of Formula (VI), o is 0. In another embodiment ofFormula (VI), o is 1. In another embodiment of Formula (VI), o is 0or 1. In another embodiment of Formula (VI), o is 0, 1, 2, or 3. Inanother embodiment of Formula (VI), o is 0, 1, 2, or 3; and R^(x), ateach occurrence, is independently selected from the group consisting of,R⁵, OR⁵, SR⁵, S(O)R⁵, SO₂R⁵, C(O)R⁵, CO(O)R⁵, OC(O)R⁵, OC(O)OR⁵, NH₂,NHR⁵, N(R⁵)₂, NHC(O)R⁵, NR⁵C(O)R⁵, NHS(O)₂R⁵, NR⁵S(O)₂R⁵, NHC(O)OR⁵,NR⁵C(O)OR⁵, NHC(O)NH₂, NHC(O)NHR⁵, NHC(O)N(R⁵)₂, NR⁵C(O)NHR⁵,NR⁵C(O)N(R⁵)₂, C(O)NH₂, C(O)NHR⁵, C(O)N(R⁵)₂, C(O)NHOH, C(O)NHOR⁵,C(O)NHSO₂R⁵, C(O)NR⁵SO₂R⁵, SO₂NH₂, SO₂NHR⁵, SO₂N(R⁵)₂, CO(O)H, C(O)H,OH, CN, N₃, NO₂, F, Cl, Br and I. In another embodiment of Formula (VI),o is 1 or 2; and R⁵, at each occurrence, is independently selected fromthe group consisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I. Inanother embodiment of Formula (VI), o is 1 or 2; R^(x), at eachoccurrence, is independently selected from the group consisting of R⁵,CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I; and R⁵, at each occurrence, isindependently selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, and cycloalkyl. Inanother embodiment of Formula (VI), o is 1; R^(x), at each occurrence,is independently selected from the group consisting of R⁵, CN, F, Cl, Brand I; and R⁵, at each occurrence, is independently selected from thegroup consisting of C₁₋₂ alkyl, and C₁ haloalkyl. In another embodimentof Formula (VI), o is 1 or 2; R^(x) is R⁵ or CN; and R⁵ is CH₃. Inanother embodiment of Formula (VI), o is 1; and R^(x) is CN. In anotherembodiment of Formula (VI), o is 1; and R^(x) is CH₃.

In one embodiment of Formula (VI), X is heteroaryl; wherein theheteroaryl represented by X is optionally substituted with one or twoR⁴;

R^(x), at each occurrence, is independently selected from the groupconsisting of R⁵, CO(O)R⁵, CO(O)H, CN, F, Cl, Br and I;

L¹ is selected from the group consisting of (CR⁶R⁷)_(q),(CR⁶R⁷)_(s)—O—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(s)—S(O)₂—(CR⁶R⁷)_(r), (CR⁶R⁷)_(s)—NR^(6A)C(O)—(CR⁶R⁷)_(r),(CR⁶R⁷)_(r), —NR^(6A)—(CR⁶R⁷)_(r), and(CR⁶R⁷)_(s)—NR^(6A)S(O)₂—(CR⁶R⁷)_(r); and

Y² is selected from the group consisting of C₃₋₁₁ branched chain alkyl,C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇ heterocyclyl;wherein the C₃₋₇ cycloalkyl, C₄₋₇ cycloalkenyl, phenyl, and C₃₋₇heterocyclyl are optionally fused to one benzene ring; wherein Y² isoptionally substituted with one, two, or three substituentsindependently selected from the group consisting of R⁸, OR⁸, SO₂R⁸,CO(O)R⁸, NHR⁸, N(R⁸)₂, C(O)H, OH, CN, NO₂, F, Cl, Br and I; or

L¹ is a bond; and

Y² is selected from the group consisting of C₃₋₇ cycloalkyl, phenyl, andC₃₋₇ heterocyclyl; wherein the C₃₋₇ cycloalkyl, phenyl, and C₃₋₇heterocyclyl represented by Y² are optionally fused to one benzene ring;wherein each Y² and each ring fused to Y² are optionally substitutedwith one substituent independently selected from the group consisting ofR⁸ and C(O)NHR⁸;

Z¹ is selected from the group consisting of

R², at each occurrence, is independently C₁₋₆ alkyl;

R⁴, at each occurrence, is independently selected from the groupconsisting of OR¹² and halogen;

R⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, aryl, andcycloalkyl;

R^(6A) is independently selected from the group consisting of hydrogenand C₁₋₆ alkyl;

R⁶ and R⁷, at each occurrence, are each independently selected from thegroup consisting of hydrogen, R¹⁵, and CO(O)R¹⁵;

R⁸, at each occurrence, is independently selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkynyl, aryl, heterocyclyl, andcycloalkyl; wherein the R⁸C₁₋₆ alkyl, and C₂₋₆ alkynyl are optionallysubstituted with one, two, or three substituents independently selectedfrom the group consisting of R¹⁶, OR¹⁶, SO₂R¹⁶, C(O)R¹⁶, N(R¹⁶)₂, OH, F,Cl, Br and I; wherein the R⁸ aryl and heterocyclyl are optionallysubstituted with one substituent independently selected from the groupconsisting of C₁₋₆ alkyl, F, Cl, Br and I;

R^(k), at each occurrence, is independently C₁₋₆ alkyl;

R¹² and R¹³, at each occurrence, are each independently C₁₋₄ alkyl;

R¹⁵, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, and aryl; wherein the R¹⁵C₁₋₄ alkyl isoptionally substituted with one substituent independently selected fromthe group consisting C₁₋₄ alkoxy, and heterocycloalkyl;

R¹⁶, at each occurrence, is independently selected from the groupconsisting of C₁₋₄ alkyl, aryl, heterocycloalkyl, and heteroaryl;

q is 1, 2, or 3;

s is 0;

r is 0, or 1;

m is 0;

n is 0, or 1;

o is 0, 1, 2, 3, or 4; and

p is 0.

Still another embodiment pertains to a compound having Formula (VI)selected from the group consisting of

-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylic    acid;-   6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylic    acid; and therapeutically acceptable salts, metabolites, prodrugs,    salts of metabolites, and salts of prodrugs thereof.    Pharmaceutical Compositions, Combination Therapies, Methods of    Treatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-xL proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-xL proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-xL proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-xL proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula (I), produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-xL proteins.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula (I) may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-xL proteins.

Compounds having Formula (I) may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthalenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds are contemplated as being embraced by this invention. Basicaddition salts of the compounds are those derived from the reaction ofthe compounds with the hydroxide, carbonate or bicarbonate of cationssuch as lithium, sodium, potassium, calcium, and magnesium.

The compounds having Formula (I) may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally or vaginally.

Therapeutically effective amounts of compounds having Formula (I) dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula (I) used to make a composition to be administered dailyto a patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula (I) may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula (I) to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered parenterally include,for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil,dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil,peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil,U.S.P. or isotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula (I) to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Abl kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,retinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B.

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-(4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE®(laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE®((G3139 or oblimersen (Bcl-2-targeting antisense oligonucleotide)),IPI-194, IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199. MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies. IRESSA®(gefitinib). TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FCl, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19 Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145 (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including P1-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap,ZACTIMATA® (vandetanib, ZD-6474) and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD41 (zanolimumab).IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX® (bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA®(fadrozole), FARESTON® (toremifene). FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol). MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib). MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents. Interferons include interferon alpha,interferon alpha-2a, interferon alpha-2b, interferon beta, interferongamma-1a, ACTIMMUNE® (interferon gamma-1b) or interferon gamma-n1,combinations thereof and the like. Other agents include ALFAFERONE®,(IFN-α), BAM-002 (oxidized glutathione), BEROMUN® (tasonermin), BEXXAR®(tositumomab), CAMPATH® (alemtuzumab), CTLA4 (cytotoxic lymphocyteantigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE®(lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-010(anti-CTLA-4), melanoma vaccine, mitumomab, molgramostim, MYLOTARG™(gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OVAREX®(oregovomab), pemtumomab (Y-muHMFG1), PROVENGE® (sipuleucel-T),sargaramostim, sizofilan, teceleukin, THERACYS® (BacillusCalmette-Guerin), ubenimex, VIRULIZIN® (immunotherapeutic, LorusPharmaceuticals). Z-100 (Specific Substance of Maruyama (SSM)), WF-10(Tetrachlorodecaoxide (TCDO)), PROLEUKIN® (aldesleukin), ZADAXIN®(thymalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-Ibritumomabtiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine. FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA).APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine). CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EPO906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula (I) as bindersto and inhibitors of anti-apoptotic Bcl-xL proteins was performed usingthe Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Finoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 μmol preloaded WANGresin/vessel on an ABI 433A peptide synthesizer using 250 μmol scaleFASTMOC™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)—OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyltrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with DCM and kept wet.150 mL of 95:4:1 dichloromethane:triisopropylsilane:trifluoroacetic acidwas flowed through the resin bed over 30 minutes. The mixture turneddeep yellow then faded to pale yellow. 100 mL of DMF was flowed throughthe bed over 15 minutes. The resin was then washed thrice with DMF andfiltered. Ninhydrin tests showed a strong signal for primary amine.

Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF andstirred or shaken at ambient temperature overnight. When complete, theresin was drained, washed thrice with DMF, thrice with (1×DCM and 1×methanol) and dried to provide an orange resin that was negative byninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water. 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 Å pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D CHEMSTATION software version A.03.04(Hewlett-Packard. Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 μ particles with a 120 Å pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

-   F-Bak: Peptide Probe Acetyl-GQVGRQLAIIGDK(6-FAM)INR—NH₂ (SEQ ID    NO:1)

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1[(M+H)⁺].

Alternative Synthesis of Peptide Probe F-Bak:Acetyl-GQVGRQLAIIGDK(6-FAM)INR-NH₂ (SEQ ID NO:1)

The protected peptide was assembeled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running FASTMOC™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer 6carboxyfluorescein-NHS was reacted with the lysine side-chain in 1% DIEAin N,N-dimethylformamide and confirmed complete by ninhydrin testing.The peptide was cleaved from the resin and side-chains deprotected bytreating with 80:5:5:5:2.5:2.5TFA/water/phenol/thioanisole/triisopropylsilane:3,6-dioxa-1,8-octanedithiol (v/v/v/v/v/v), and the crude peptide wasrecovered by precipitation with diethyl ether. The crude peptide waspurified by reverse-phase high-performance liquid chromatography, andits purity and identity were confirmed by analytical reverse-phasehigh-performance liquid chromatography and matrix-assistedlaser-desorption mass-spectrometry (m/z=2137.1 ((M+H)+)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

The measurement of competition of compounds of Formula (I) with F-Bakfor a Bcl-2 family protein (Bcl-xL) binding site using a Time ResolvedFluorescence Resonance Energy Transfer (TR-FRET) binding assay:

Test compounds were serially diluted in DMSO starting at 50 M (2×starting concentration; 10% DMSO) and 10 μL transferred into a 384-wellplate. Then 10 μL of a protein/probe/antibody mix is added to each wellat final concentrations listed in Table 1.

TABLE 1 Protein Probe Antibody Protein Probe (nM) (nM) Antibody (nM)GST-Bcl- F-Bak 1 100 Tb-anti- 1 xL (GQVGRQLAIIGDK GST (6-FAM)INR-amide)SEQ ID NO: 1

The samples are then mixed on a shaker for 1 minute then incubated foran additional 2 hours at room temperature. For each assay plate, aprobe/antibody and protein/antibody/probe mixture were included as anegative and a positive control, respectively. Fluorescence was measuredon the ENVISION plate reader (Perkin Elmer) using a 340/35 nm excitationfilter and 520/525 (F-Bak) and 495/510 nm (Tb-labeled anti-his antibody)emission filters. Dissociation constants (K_(i)) were determined usingWang's equation (Wang, Z.X. An 20 exact mathematical expression fordescribing competitive binding of two different ligands to proteinmolecule. FEBS Lett. 1995 360:111-114). The TR-FRET assay can beperformed in the presence of varying concentrations of human serum (HS)or fetal bovine serum (FBS). TR-FRET assay results (K_(i), in nanomolar)for representative compounds of Formula (I) are provided below in Table2.

For comparison, the measurement of the competition of compounds ofFormula (I) for other Bcl-2 family protein binding sites (e.g., Bcl-2)using the TR-FRET binding assay was accomplished by substitutingGST-Bcl-xL in the TR-FRET assay with other GST-labeled protein, e.g.,GST-Bcl-2, prepared in-house.

In one embodiment, compounds of Formula (I) selectively inhibit theBcl-2 family protein, Bcl-x_(L), over other Bcl-2 family proteins, suchas Bcl-2. For comparison, data (K_(i) in micromolar) from themeasurement of the competition by certain compounds of Formula (I)(i.e., Examples 20, 43, 49, 82, 99, 107, 117, 130, 134, 148 159, 176 and185 in Table 3) with F-Bak for the Bcl-2 binding site using the TR-FRETbinding assay are 0.070, 0.023, 0.039, 0.033, 0.033, 0.056, 0.021,0.076, 0.024, 0.075, 0.272, 0.177 and 0.014, respectively.

FL5.12 Cellular Assay

The efficacy of the compounds of Formula (I) can also be determined incell-based killing assays using a variety of cell lines and mouse tumormodels. For example, their activity on cell viability can be assessed ona panel of cultured tumorigenic and non-tumorigenic cell lines, as wellas primary mouse or human cell populations. In one exemplary set ofconditions, mouse FL5.12 cells transfected with Bcl-XL were culturedunder standard conditions in RPMI with 2 mM glutamine, 1% 100 mM sodiumpyruvate, 2% 1 M HEPES, 4 μL/L of β-mercaptoethanol, 1%penicillin-streptomycin, 10% FBS, and 10% WEHI-3B conditioned media (forIL-3). For assaying the compound activity, the cells were exchanged intoan IL-3-depleted deprivation media, which was identical to the growthmedia except for the absence of FBS and WEHI-3B conditional media, for 2days. Then the cells were exchanged to 3% FBS assay media (RPMI with 2mM glutamine, 1% 100 mM sodium pyruvate, 2% 1 M HEPES, 4 μL/L ofβ-mercaptoethanol, 1% penicillin-streptomycin, 3% FBS). Compounds inseries dilutions were added, and the cells were cultured for 24 hours.Compounds in series dilutions were added, and the cells were culturedfor 24 hours. Cell viability was assayed using the CellTiter-Glo assay(Promega Corp., Madison, Wis.) according to the manufacturerinstructions. Individual determinations were the result of duplicatevalues. Cell viability assay results (EC₅₀ in nanomolar) forrepresentative compounds are provided below in Table 2.

TABLE 2 In Vitro Data TR-FRET binding FL5.12 Bcl-xL, EX Bcl-xL Ki (nM)IL3, EC 50 (nM) 1 12 425 2 205 n.d. 3 258 >1000 4 115 n.d. 5 19 4086 >1000 n.d. 7 312 n.d. 8 98 n.d. 9 6 378 10 68 n.d. 11 180 >1000 12 851 13 12 498 14 12 >1000 15 35 >1000 16 159 n.d. 17 31 >1000 18 38 62119 28 398 20 2 13 21 183 >1000 22 6 214 23 182 >1000 24 64 >1000 25 8377 26 167 >1000 27 315 >1000 28 33 >1000 29 18 >1000 30 2 298 3118 >1000 32 5 216 33 169 >1000 34 23 907 35 91 n.d. 36 8 >1000 37 17 34738 48 >1000 39 56 >1000 40 16 570 41 1 11 42 2 233 43 0.9 4 44 17 >100045 19 >1000 46 9 >1000 47 16 881 48 7 >1000 49 0.6 12 50 99 >1000 51122 >1000 52 18 570 53 14 387 54 15 501 55 18 317 56 24 583 57 14 741 58174 >1000 59 424 >1000 60 5 219 61 11 380 62 61 >1000 63 2 27 6461 >1000 65 393 >1000 66 3 60 67 7 106 68 279 >1000 69 91 >1000 70 5 5871 18 n.d. 72 28 >1000 73 0.9 8 74 6 335 75 28 919 76 29 >1000 77 10 43178 379 >1000 79 0.5 19 80 4 253 81 0.6 37 82 0.5 8 83 0.5 >1000 84 0.712 85 0.7 12 86 2 4 87 4 124 88 3 229 89 0.5 23 90 1 n.d. 91 0.9 30 92 256 93 16 295 94 5 253 95 11 542 96 12 620 97 2 <1 98 2 421 99 0.9 60 1003 66 101 0.4 <1 102 <0.1 n.d. 103 0.6 >1000 104 14 >1000 105 7 >1000 1060.1 234 107 0.2 10 108 9 >1000 109 49 >1000 110 0.3 90 111 21 >1000 1120.7 523 113 19 >1000 114 0.2 220 115 5 916 116 <0.1 667 117 <0.1 131 1180.2 361 119 <0.1 762 120 0.4 859 121 0.1 87 122 117 >1000 123 <0.1 16124 <0.1 57 125 0.3 527 126 47 >1000 127 2 >1000 128 7 >1000 129 <0.1 18130 <0.1 30 131 <0.1 9 132 3 n.d. 133 0.9 n.d. 134 <0.1 0.9 135 78 >1000136 1.4 >1000 137 1.5 363 138 <0.1 >1000 139 0.4 >1000 140 2.3 >1000 1411 433 142 0.5 >1000 143 <0.1 19 144 <0.1 213 145 <0.1 0.2 146 <0.1 11147 <0.1 1 148 <0.1 13 149 0.3 986 150 0.2 339 151 <0.1 0.6 152 <0.1 1153 0.3 587 154 <0.1 15 155 <0.1 7 156 0.2 15 157 <0.1 0.3 158 <0.1 364159 0.2 31 160 <0.1 14 161 <0.1 7 162 <0.1 5 163 0.4 211 164 <0.1 308165 <0.1 9 166 <0.1 30 167 <0.1 81 168 <0.1 14 169 <0.1 10 170 <0.1 0.5171 <0.1 97 172 <0.1 1 173 <0.1 0.1 174 <0.1 210 175 <0.1 33 176 <0.1 10177 <0.1 24 178 <0.1 0.2 179 <0.1 6 181 <0.1 241 182 0.2 6 183 0.7 507184 <0.1 2 185 <0.1 n.d. 186 <0.1 n.d. 187 0.4 318 188 0.5 546 EX =Example, n.d. = no data available

Molt-4 Cellular Assay

Molt-4 (ATCC, Manassas, Va.) human acute lymphoblastic leukemia cellswere plated 50,000 cells per well in 96-well tissue culture plates in atotal volume of 100 μL tissue culture medium supplemented with 10% humanserum (Invitrogen, Carlsbad, Calif.) and treated with a 3-fold serialdilution of the compounds of interest from 5 μM to 0.020 μL. Eachconcentration was tested in duplicate at least 3 separate times. Thenumber of viable cells following 48 hours of compound treatment wasdetermined using the CellTiter 96® Aqueous non-radioactive cellproliferation MTS assay according to manufacturer's recommendations(Promega Corp., Madison, Wis.). Molt-4 cell viability results (i.e. EC₅₀in micromolar) for certain compounds of Formula (I), (i.e., Examples 81,82, 84, 87, 124, 130, 134, 145, 151, 152, 166, 179, and 186 in Table 2),are 0.33, 0.135, 0.501, 1.2, 2.7, 0.532, 0.029, 0.081, 0.014, 0.006,0.586, 0.493, and 0.006, respectively.

Single Dose Pharmacokinetics

The single dose pharmacokinetics of select compounds were evaluated inSprague-Dawley rats (Charles River) after a 5 mg/kg oral dose (n=3) (10%DMSO in PEG-400) administered by gavage or by 5 mg/kg IV bolus dose(n=3) (10% DMSO in PEG-400). Compound and the internal standard wereseparated from each other and coextracted contaminants on a 50 mm×3 mmKeystone Betasil CN 5 μm column with an acetonitrile/0.1%trifluoroacetic acid mobile phase (50:50, by volume) at a flow rate of0.7 mL/min. Analysis was performed on a Sciex API3000 biomolecular massanalyzer with a heated nebulizer interface. Compound and internalstandard peak areas were determined using Sciex MacQuan software. Theplasma drug concentration of each sample was calculated by least-squareslinear regression analysis (nonweighted) of the peak area ratio(parent/internal standard) of the spiked plasma standards versusconcentration. The plasma concentration data were submitted tomultiexponential curve fitting using WinNonlin.3. The area under theplasma concentration-time curve was calculated using the lineartrapezoidal rule for the plasma concentration-time profiles.

In pharmacology, bioavailability (BA) is a subcategory of absorption andis used to describe the fraction of an administered dose of unchangeddrug that reaches the systemic circulation, one of the principalpharmacokinetic properties of drugs. By definition, when a medication isadministered intravenously, its bioavailability is 100% (see Griffin. J.P. The Textbook of Pharmaceutical Medicine (6th Ed.). New Jersey: BMJBooks). However, when a medication is administered via other routes(such as orally), its bioavailability generally decreases (due toincomplete absorption and first-pass metabolism) and may vary frompatient to patient. Bioavailability is one of the essential tools inpharmacokinetics, as bioavailability must be considered when calculatingdosages for non-intravenous routes of administration. One way tocalculate bioavailability of a drug or agent is by dividing the plasmaconcentration following an oral dose by the concentration following anintravenous dose. The oral bioavailability (as represented by % F) inSprague-Dawley rats for representative compounds of the invention areprovided below in Table 3.

In the drug discovery setting, it is generally accepted that Lipinski's“rule of 5” predicts that poor oral absorption or poor permeation islikely when two or more of the following metrics are satisfied: i) thereare more than 5 hydrogen bond donors, ii) the molecular weight isgreater than 500, iii) there are greater than 10 hydrogen bond acceptors(expressed as the sum of nitrogen and oxygen atoms), or iv) thecalculated Log P (c Log P) is greater than 5 (Lipinski et al. Adv. DrugDel. Rev. 2001, 3-26). Indeed, the combination of high molecular weight(>500) and high c Log P (>5) is the best predictor of poor absorption orpermeation. Compounds described herein generally exceed the recommendedranges pertaining to molecular weight (>500) and c Log P (>5), as shownin Table 3. It is notable, therefore, that Examples described hereinhave acceptable oral bioavailability in rats (as defined by % F>10, seeMartin J. Med. Chem. 2005, 48, 3164), as illustrated in Table 3.

TABLE 3 PK Data, Rat p.o. dose Molecular F (%), EXAMPLE # weight cLogPdose 5 600.7 6.6 19, 5 mpk 12 614.7 6.7 29, 5 mpk 19 600.7 6.5 22, 5 mpk20 600.7 6.5 17, 5 mpk 22 656.8 6.1 27, 5 mpk 23 572.6 6.5 20, 5 mpk 25621.1 7.0 24, 5 mpk 37 612.7 6.7 29, 5 mpk 63 592.7 6.8 20, 5 mpk 70632.8 7.8 21, 5 mpk 73 642.7 6.8 19, 5 mpk 74 660.7 7.3 23, 5 mpk 82620.8 7.9 45, 5 mpk 88 650.8 7.0 23, 5 mpk 89 674.8 6.3 13, 5 mpk 90664.8 7.2 44, 5 mpk 91 616.7 7.2 16, 5 mpk 93 644.7 6.4 33, 5 mpk 97678.8 7.7 33, 5 mpk 99 714.8 6.7 19, 5 mpk 101 680.8 6.7 40, 5 mpk 103598.7 8.4 39, 5 mpk 106 596.7 8.4 24, 5 mpk 107 616.8 9.6 14, 5 mpk 110612.7 8.6 36, 5 mpk 114 618.7 8.6 38, 5 mpk 119 622.7 8.4 54, 5 mpk 122587.7 5.8 40, 5 mpk 129 624.7 7.0 17, 5mpk 130 630.6 7.8 32, 5 mpk 131713.9 6.0 11, 5 mpk 134 678.9 8.0 50, 5 mpk 146 692.9 8.4 16, 5 mpk 147692.9 8.5 37, 5 mpk 148 756.0 7.0 18, 5 mpk 151 694.9 7.5 30, 1 mpk 154608.72 5.7 22, 1 mpk 156 625.8 8.8 39, 1 mpk 157 664.8 8.1 30, 1 mpk

Data in Table 2 and cited Molt-4 data show the utility of compounds ofthe invention to functionally inhibit anti-apoptotic Bcl-xL protein in acellular context. The ability of compounds to kill FL5.12 cellsover-expressing Bcl-xL or human tumor cell lines that are dependant uponBcl-xL such as Molt-4 cells is a direct measure of the compound'sability to inhibit anti-apoptotic Bcl-xL protein function. Compounds ofthe invention are very effective in killing FL5.12 cells over-expressingBcl-xL or human tumor cell lines that are dependant upon Bcl-xL such asMolt-4 cells as demonstrated by low EC₅₀ values. In addition, asdemonstrated in Table 3, compounds of the invention have acceptable oralbioavailability in preclinical rodent studies, and therefore may findutility as orally-dosed therapeutics in a clinical setting.

Overexpression of Bcl-xL proteins correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordomna,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophobalstic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcomna, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula (I) would inhibitgrowth of cells expressing Bcl-xL proteins derived from a pediatriccancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia areata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,common varied immunodeficiency (common variable hypogammaglobulinaemia),conjunctivitis, connective tissue disease associated interstitial lungdisease, contact dermatitis, Coombs positive haemolytic anaemia, corpulmonale, Creutzfeldt-Jakob disease, cryptogenic autoimmune hepatitis,cryptogenic fibrosing alveolitis, culture negative sepsis, cysticfibrosis, cytokine therapy associated disorders, Crohn's disease,dementia pugilistica, demyelinating diseases, dengue hemorrhagic fever,dermatitis, scleroderma, dermatologic conditions,dermatomyositis/polymyositis associated lung disease, diabetes, diabeticarteriosclerotic disease, diabetes mellitus, Diffuse Lewy body disease,dilated cardiomyopathy, dilated congestive cardiomyopathy, discoid lupuserythematosus, disorders of the basal ganglia, disseminatedintravascular coagulation, Down's Syndrome in middle age, drug-inducedinterstitial lung disease, drug-induced hepatitis, drug-induced movementdisorders induced by drugs which block CNS dopamine, receptors, drugsensitivity, eczema, encephalomyelitis, endocarditis, endocrinopathy,enteropathic synovitis, epiglottitis, Epstein-Barr virus infection,erythromelalgia, extrapyramidal and cerebellar disorders, familialhematophagocytic lymphohistiocytosis, fetal thymus implant rejection,Friedreich's ataxia, functional peripheral arterial disorders, femaleinfertility, fibrosis, fibrotic lung disease, fungal sepsis, gasgangrene, gastric ulcer, giant cell arteritis, glomerular nephritis,glomerulonephritides, Goodpasture's syndrome, goitrous autoimmunehypothyroidism (Hashimoto's disease), gouty arthritis, graft rejectionof any organ or tissue, graft versus host disease, gram negative sepsis,gram positive sepsis, granulomas due to intracellular organisms, group Bstreptococci (GBS) infection, Grave's disease, haemosiderosis associatedlung disease, hairy cell leukemia, hairy cell leukemia,Hallerrorden-Spatz disease, Hashimoto's thyroiditis, hay fever, hearttransplant rejection, hemachromatosis, hematopoietic malignancies(leukemia and lymphoma), hemolytic anemia, hemolytic uremicsyndrome/thrombolytic thrombocytopenic purpura, hemorrhage,Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B, Hepatitis C, HIVinfection/HIV neuropathy, Hodgkin's disease, hypoparathyroidism,Huntington's chorea, hyperkinetic movement disorders, hypersensitivityreactions, hypersensitivity pneumonitis, hyperthyroidism, hypokineticmovement disorders, hypothalamic-pituitary-adrenal axis evaluation,idiopathic Addison's disease, idiopathic leucopaenia, idiopathicpulmonary fibrosis, idiopathic thrombocytopaenia, idiosyncratic liverdisease, infantile spinal muscular atrophy, infectious diseases,inflammation of the aorta, inflammatory bowel disease, insulin dependentdiabetes mellitus, interstitial pneumonitis, iridocyclitis/uveitis/opticneuritis, ischemia-reperfusion injury, ischemic stroke, juvenilepernicious anaemia, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, Kawasaki's disease, kidneytransplant rejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myelodyplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, Reiter's disease, renal disease NOS,renovascular hypertension, reperfusion injury, restrictivecardiomyopathy, rheumatoid arthritis associated interstitial lungdisease, rheumatoid spondylitis, sarcoidosis, Schmidt's syndrome,scleroderma, senile chorea, Senile Dementia of Lewy body type, sepsissyndrome, septic shock, seronegative arthropathies, shock, sickle cellanemia, Sjögren's disease associated lung disease, Sjögren's syndrome,skin allograft rejection, skin changes syndrome, small bowel transplantrejection, sperm autoimmunity, multiple sclerosis (all subtypes), spinalataxia, spinocerebellar degenerations, spondyloarthopathy, sporadic,polyglandular deficiency type I, sporadic polyglandular deficiency typeII, Still's disease, streptococcal myositis, stroke, structural lesionsof the cerebellum, Subacute sclerosing panencephalitis, sympatheticophthalmia, Syncope, syphilis of the cardiovascular system, systemicanaphylaxis, systemic inflammatory response syndrome, systemic onsetjuvenile rheumatoid arthritis, systemic lupus erythematosus, systemiclupus erythematosus-associated lung disease, systemic sclerosis,systemic sclerosis-associated interstitial lung disease, T-cell or FABALL, Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimentals

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄; 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo[5.4.0]undec-7-ene: DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppbmeans 1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

Schemes

As shown in Scheme 1, compounds of formula (1), wherein R¹, R², n, and mare as described herein, can be reacted with compounds of formula (2)wherein X is as described herein, in the presence of a carboxylactivating agent such as but not limited toN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride, and acatalyst such but not limited to 4-dimethylaminopyridine, to providecompounds of formula (3). The reaction is typically performed at roomtemperature in a solvent such as but not limited to dichloromethane.Compounds of formula (4) can be prepared by reacting compounds offormula (3) with an acid such as but not limited to hydrochloric acid ina solvent such as but not limited to 1,4-dioxane. Compounds of formula(4) can be reacted with compounds of formula (5), wherein Z¹, R³ and pare as described herein and X³ is chloro or fluoro, in the presence of abase such as but not limited to cesium carbonate, to provide compoundsof formula (6). The reaction is typically performed at an elevatedtemperature in a solvent such as but not limited toN,N-dimethylacetamide. Compounds of formula (7) can be prepared byreacting compounds of formula (6) with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran, in thepresence of a base such as but not limited to triethylamine, and acatalyst such as but not limited to[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane. The reaction is typically performed at elevatedtemperature and with the addition of a solvent such as but not limitedto acetonitrile. Additionally, the reaction may be performed in amicrowave reactor.

After preparation as described in Scheme 1, compounds of formula (6) canbe reacted with a boronic acid (or the boronate equivalent) of formula(8) or an organotin or organozinc halide compound of formula (8a)wherein Y¹, L¹, and Y² are as described herein, and M is tributyltin ora zince halide, under Suzuki, Stille, or Negishi coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (I). Alternatively, compoundsof formula (7), which can be prepared from compounds of formula (6) asdescribed in Scheme 1, can be reacted with compounds of formula (9)wherein X¹ is a triflate or halide, and Y¹, L¹, and Y¹ are as describedherein, under Suzuki coupling conditions known to those skilled in theart and readily available in the literature to provide compounds offormula (I).

As shown in Scheme 3, pyrazoles of formula (10), wherein Rx^(x1) ishydrogen or a substituent on Y¹ as described herein, can be reacted withalcohols of formula (11), wherein L¹ and Y² are as described herein, andcyanomethylenetributylphosphorane, to provide compounds of formula (12).The reaction is typically performed at ambient temperature in a solventsuch as but not limited to toluene. Compounds of formula (14) can beprepared by adding compounds of formula (13) wherein R¹² is anappropriate substituent as described herein for substituents on Y¹, andX² is a halide, to a cold solution of compounds of formula (12) treatedwith n-butyllithium in hexanes. The reaction is typically performed in asolvent such as but not limited to tetrahydrofuran. Compounds of formula(14) can be treated with N-bromosuccinimide or N-iodosuccinimide toprovide compounds of formula (15), wherein X⁴ is bromo or iodo. Thereaction is typically performed in a solvent such asN,N-dimethylformamide. Compounds of formula (15) can be reacted withcompounds of formula (7) under Suzuki coupling conditions known to thoseskilled in the art and readily available in the literature to providecompounds of formula (17), which are representative of compounds offormula (I). Alternatively, compounds of formula (15) can be reactedwith triisopropyl borate, in the presence of n-butyllithium in hexanes,followed by pinacol to provide compounds of formula (18). The additionsare typically performed at low temperature in a solvent such as but notlimited to tetrahydrofuran, toluene, or mixtures thereof. Alternatively,compounds of the formula (15) can be treated with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a palladiumcatalyst system such as but not limited to bis(acetonitrile)palladiumdichloride and SPhos in a solvent such as but not limited to 1,4-dioxaneto provide compounds of the formula 18. The reaction is typicallyperformed at elevated temperature. Compounds of formula (18) can bereacted with compounds of formula (6) under Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (17), which arerepresentative of compounds of formula (I).

Pyrroles of formula (21) wherein R^(x1), R^(x2), and R^(x3) are hydrogenor are as described herein for substituents on Y¹, can be reacted withalcohols of formula (11), wherein Y² and L¹ are as described herein, andcyanomethylenetributylphosphorane, to provide compounds of formula (22).The reaction is typically performed at ambient temperature in a solventsuch as but not limited to toluene. Compounds of formula (22) can betreated with N-bromosuccinimide to provide compounds of formula (23).The reaction is typically performed in a solvent such asN,N-dimethylformamide. Compounds of formula (23) can be reacted withtriisopropyl borate, in the presence of n-butyllithium in hexanes,followed by pinacol to provide compounds of formula (24). The additionsare typically performed at low temperature in a solvent such as but notlimited to tetrahydrofuran, toluene, or mixtures thereof. Alternatively,compounds of the formula (23) can be treated with4,4,5,5-tetramethyl-1,3,2-dioxaborolane in the presence of a palladiumcatalyst system such as but not limited to bis(acetonitrile)palladiumdichloride and SPhos in a solvent such as but not limited to 1,4-dioxaneto provide compounds of the formula (24). The reaction is typicallyperformed at an elevated temperature. Compounds of formula (24) can bereacted with compounds of formula (6) under Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature to provide compounds of formula (25), which arerepresentative of compounds of formula (I). Alternatively, compounds offormula (23) can be reacted with compounds of formula (7) under Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature to provide compounds of formula (25), whichare representative of compounds of formula (I).

Compounds of formula (22A), wherein Z is O, a substituted orunsubstituted N, or a substituted or unsubstituted C: R^(x1) is hydrogenor is as described herein for substituents on Y²; R¹⁴ is alkyl; and n is0, 1, or 2; can be added to a cooled solution of lithiumdiisopropylamide, followed by the addition of compounds of formula(23A); wherein R^(x2) is an appropriate substituent as described hereinfor substituents on Y¹, and X¹ is a halide; to provide compounds offormula (23B). The reaction is typically performed at low temperaturebefore warming to ambient temperature in a solvent such as but notlimited to tetrahydrofuran. Compounds of formula (23B) can be reactedwith LiAlH₄ to provide compounds of formula (24B). The reaction istypically performed at an elevated temperature in a solvent such as butnot limited to diethyl ether. Compounds of formula (25A) can be preparedby reacting compounds of formula (24B) with compounds of formula (24A)wherein Y¹ is as described herein; andcyanomethylenetributylphosphorane. The reaction is typically performedat ambient temperature in a solvent such as but not limited to toluene.Compounds of formula (25A) can be processed in a manner similar tocompounds of formula (12) in Scheme 3 and compounds of formula (22) inScheme 4 to provide compounds of formula (I).

As shown in Scheme 6, compounds of formula (27), wherein R^(x1) ishydrogen or a substituent on Y¹ as described herein, can be prepared byreacting compounds of formula (26) with trimethylsulfonium iodide, inthe presence of potassium tert-butoxide. The reaction is typicallyperformed at ambient temperature in an anhydrous solvent such as but notlimited to dimethylsulfoxide. Compounds of formula (27) can be added toa mixture of compounds of formula (24A) and a base such as but notlimited to cesium carbonate, to provide compounds of formula (28). Thereaction is typically performed at elevated temperature in a solventsuch as but not limited to N,N-dimethylformamide, and may be performedin a microwave reactor. Compounds of formula (28) can be treated withsodium hydride, followed by the addition of compounds of formula (13) toprovide compounds of formula (29). The reaction is typically performedat ambient temperature in a solvent such as but not limited totetrahydrofuran, and may involve the use of hexamethylphosphoramide.Compounds of formula (29) can be processed in a manner similar tocompounds of formula (12) in Scheme 3 and compounds of formula (22) inScheme 4 to provide compounds of formula (I).

Compounds of formula (33) wherein M is a boronic acid, boronate, ortributlytin attached to Y¹ and Y¹, L¹, and Y² are as described herein,and X¹ is chloro or fluoro; can be reacted with compounds of formula(32) wherein Z¹, R³, and p are as described herein, under Suzuki orStille coupling conditions known to those skilled in the art and readilyavailable in the literature to provide compounds of formula (34).Compounds of formula (34) can be reacted with compounds of formula (4),in the presence of a base such as but not limited to cesium carbonate,to provide compounds of formula (I). The reaction is typically performedat an elevated temperature in a solvent such as but not limited toN,N-dimethylacetamide.

Triazoles of formula (36) can be prepared by reacting azides of formula(35), wherein L¹ and Y² are as described herein, with compounds offormula (36A) wherein R^(x2) is alkyl, under conditions known to thoseskilled in the art and readily available in the literature. Compounds offormula (37), wherein Z¹ is as described herein, can be reacted withcompounds of formula (36) under Stille coupling conditions known tothose skilled in the art and readily available in the literature toprovide compounds of formula (38). Compounds of formula (4), wherein R¹,R², X, m and n are as described herein, can be reacted with compounds offormula (38), in the presence of a base such as but not limited tocesium carbonate, to provide compounds of formula (39), which arerepresentative of compounds of formula (I). The reaction is typicallyperformed at an elevated temperature in a solvent such as but notlimited to N,N-dimethylacetamide.

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), ACD/ChemSketch Version 12.01 (13May 2009), Advanced Chemistry Development Inc., Toronto, Ontario), orChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.). Intermediateswere named using ChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

EXAMPLES Example 16-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 1A tert-butyl8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid(6.8 g) and benzo[d]thiazol-2-amine (5.52 g) in dichloromethane (80 mL)was added 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(9.4 g) and 4-dimethylaminopyridine (6 g). The mixture was stirred atroom temperature overnight. The reaction mixture was diluted withdichloromethane (400 mL), washed with 5% aqueous HCl, water, and brine,and dried over Na₂SO₄. The mixture was filtered and the filtrate wasconcentrated under reduced pressure to provide the title compound.

Example 1BN-(benzo[d]thiazol-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamidedihydrochloride

To a solution of EXAMPLE 1A (8.5 g) in dichloromethane (80 mL) was added2N HCl in ether (80 mL). The reaction mixture was stirred at roomtemperature overnight and concentrated under reduced pressure to providethe title compound.

Example 1C tert-butyl 3-bromo-6-chloropicolinate

Tosyl chloride (7.7 g) was added to a solution of 2-chloro-5-bromopicolinic acid (4 g) and pyridine (9.2 mL) in t-butanol (33 mL) at 0° C.The reaction was then stirred at room temperature for 12 hours. NaHCO₃(aqueous, saturated) was then added and the mixture was extracted threetimes with ethyl acetate. The combined organic phases were washed withbrine and dried over Na₂SO₄. Filtration and evaporation of the organicsolvent provided the title compound which was used in the next stepwithout further purification.

Example 1D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

EXAMPLE 1C (0.736 g), EXAMPLE 1B (1.62 g), and Cs₂CO₃ (4.1 g) werestirred in 12 mL of anhydrous N,N-dimethylacetamide at 120° C. for 12hours. The cooled reaction mixture was then diluted with ethyl acetateand 10% citric acid. The organic phase was washed three times withcitric acid, once with water and brine, and dried over Na₂SO₄.Filtration and concentration afforded crude material, which waschromatographed on silica gel using 0-40% ethyl acetate in hexanes toprovide the title compound.

Example 1E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 1D (0.113 g),1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.063 g),tetrakis(triphenylphosphine)palladium(0) (0.023 g) and CsF(0.091 g) in 1,2-dimethoxyethane (2 mL) and methanol (1 mL) was heatedat 120° C. for 30 minutes under microwave heating conditions. Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel eluting with 35% ethyl acetate in hexanesto afford the title compound.

Example 1F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

EXAMPLE 1E (100 mg) in dichloromethane (3 mL) was treated withtrifluoroacetic acid (3 mL). The reaction mixture was stirred at roomtemperature for 4 hours. The volatiles were removed under reducedpressure. The residue was purified by Prep HPLC using Gilson systemeluting with 20-80% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The desired fractions were combined andfreeze-dried to provide the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.92 (s, 1H),7.80 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.67 (s, 1H),7.42-7.50 (m, 2H), 7.23-7.38 (m, 7H), 6.94 (d, 1H), 5.33 (s, 2H), 4.94(s, 2H), 3.86 (t, 2H), 3.00 (t, 2H).

Example 26-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 2A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting4-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinefor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 1E.

Example 2B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 2A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.70 (d, 2H), 8.04 (d, 1H), 8.02 (s, 1H), 7.80 (d, 1H), 7.73 (d,1H), 7.67 (s, 1H), 7.62 (d, 1H), 7.34-7.50 (m, 6H), 6.97 (d, 1H), 5.59(s, 2H), 4.96 (s, 2H), 3.87 (t, 2H), 3.01 (t, 2H).

Example 36-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 3A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinefor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 1E.

Example 3B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 3A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.70 (d, 2H), 8.62-8.63 (m, 2H), 8.04 (d, 1H), 8.00 (s, 1H), 7.90(d, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.85-7.62 (m, 3H), 7.34-7.50 (m,5H), 6.95 (d, 1H), 5.46 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t,2H).

Example 46-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 4A 1-(benzyloxy)-4-(bromomethyl)benzene

A mixture of (4-(benzyloxy)phenyl)methanol (2.14 g) and lithium bromide(1.0 g) in N,N-dimethylformamide (20 mL) was cooled to 0° C. To thissolution was added PBr₃ (1.0 mL). The solution was stirred at roomtemperature for 2 hours. The reaction mixture was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with additionalethyl acetate, twice. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified by flash column chromatography on silica gel eluting with 5%ethyl acetate in hexanes to provide the title compound.

Example 4B1-(4-(benzyloxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

A mixture of EXAMPLE 4A (0.54 g) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) inN,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution wasadded 60% sodium hydride (0.096 g). The solution was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenwater and ethyl acetate. The aqueous layer was extracted with additionalethyl acetate twice. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedby flash column chromatography on silica gel eluting with 25% ethylacetate in hexanes to provide the title compound.

Example 4C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE of 4B for3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinein EXAMPLE 1E.

Example 4D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-hydroxybenzyl)-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 4C (0.05 g) and 5% palladium on carbon (0.1 g) inethanol (5 mL) was treated with a balloon of hydrogen. The reactionmixture was stirred overnight. The solid was removed by filtration, andfiltrate was concentrated to provide the title compound.

Example 4E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 4D for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.61 (d,1H), 7.54 (s, 1H), 7.46-7.50 (m, 1H), 7.42-7.46 (m, 1H), 7.34-7.38 (m,2H), 7.08-7.12 (m, 2H), 6.93 (d, 1H), 6.69-6.73 (m, 2H), 5.17 (s, 2H),4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).

Example 56-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 5A

The title compound was prepared by substituting (1-bromoethyl)benzenefor EXAMPLE 4A in EXAMPLE 4B.

Example 5B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(1-phenylethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 5A for3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinein EXAMPLE 1E.

Example 5C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 5B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.79 (s,1H), 7.97 (d, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.65 (d, 1H), 7.54 (d,1H), 7.50 (s, 1H), 7.55-7.56 (m, 1H), 7.24-7.30 (m, 4H), 7.17-7.20 (m,3H), 6.97 (d, 1H), 5.54 (q, 1H), 4.87 (s, 2H), 3.79 (t, 2H), 2.93 (t,2H).

Example 66-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{4-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 6A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 4C (0.30 g) and(2-(chloromethoxy)ethyl)trimethylsilane (0.094 g) in tetrahydrofuran (4mL) was treated with triethylamine (0.122 g) at room temperature. Thereaction was stirred for 1 hour. The reaction mixture was partitionedbetween water and ethyl acetate. The aqueous layer was extracted withadditional ethyl acetate twice. The combined organic layers were washedwith brine, dried over MgSO₄, filtered, and concentrated. The residuewas purified by flash column chromatography on silica gel eluting with5% ethyl acetate in hexanes to provide the title compound.

Example 6B tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-hydroxybenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 6A for EXAMPLE4C in EXAMPLE 4D.

Example 6C tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 6B (0.18 g), 2-(dimethylamino)ethanol (0.102 g),and triphenylphosphine (0.299 g) in tetrahydrofuran (3 mL) was stirredfor 5 minutes at 0° C. To this solution was added (E)-di-tert-butyldiazene-1,2-dicarboxylate (0.263 g). The reaction mixture was stirred atroom temperature for 16 hours. The solvent was removed, and the residuewas purified by flash column chromatography on silica gel using 5-50%ethyl acetate in hexanes to provide the title compound.

Example 6D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{4-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

EXAMPLE 6C (0.08 g) in dichloromethane (3 mL) was treated withtrifluoroacetic acid (3 mL). The reaction mixture was stirred at roomtemperature for 16 hours. The volatiles were removed under reducedpressure. The residue was purified by Prep HPLC using a Gilson systemeluting with 20-80% acetonitrile in 0.1% water. The desired fractionswere combined and freeze-dried to provide the title compound. ¹H NMR(500 MHz, dimethylsulfoxide-d₆) δ ppm 9.55 (s, 1H), 8.03 (d, 1H), 7.88(s, 1H), 7.78 (d, 1H), 7.68 (d, 1H), 7.60 (d, 1H), 7.54 (s, 1H),7.41-7.48 (m, 2H), 7.33-7.36 (m, 2H), 7.25 (d, 2H), 6.96 (d, 2H), 6.93(d, Hz, 1H), 5.24 (s, 2H), 4.94 (s, 2H), 4.93 (s, 2H), 4.26-4.28 (m,2H), 3.85 (t, 2H), 2.97-2.99 (m, 2H), 2.83 (s, 6H).

Example 73-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(5,6-difluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid Example 7A methyl2-(5-bromo-6-(tert-butoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate

A solution of methyl 1,2,3,4-tetrahydroisoquinoline-8-carboxylate (1.00g), EXAMPLE 1C (1.68 g) and cesium carbonate (2.56 g) was stirredtogether in N,N-dimethylacetamide (10 mL) at 110° C. overnight. Thereaction was cooled, diluted with ethyl acetate (50 mL) and washed withwater (2×25 mL) and brine (25 mL), dried over magnesium sulfate,filtered, and concentrated. Silica gel chromatography using 1-30% ethylacetate in hexanes provided the title compound.

Example 7B methyl2-(5-(1-benzyl-1H-pyrazol-4-yl)-6-(tert-butoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylate

The title compound was prepared by substituting EXAMPLE 7A for EXAMPLE1D in EXAMPLE 1E.

Example 7C2-(5-(1-benzyl-1H-pyrazol-4-yl)-6-(tert-butoxycarbonyl)pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic

To a solution of EXAMPLE 7B (0.565 g) in tetrahydrofuran (4 mL) andmethanol (2 mL) was added NaOH (1.292 ml, 1 M) and the reaction wasstirred at room temperature overnight. The reaction was diluted withethyl acetate (50 mL) and quenched with 1N aqueous HCl (1.3 mL) anddiluted with water (20 mL). The organic layer was separated, dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatographyeluting with a gradient of 0.5% to 3% methanol/dichloromethane providedthe title compound.

Example 7D tert-butyl3-(1-benzyl-1H-pyrazol-4-yl)-6-(8-(5,6-difluorobenzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

EXAMPLE 7C (0.086 g), 5,6-difluorobenzo[d]thiazol-2-amine (0.034 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.048 g)and 4-dimethylaminopyridine (0.041 g) were combined together indichloromethane (1 mL) and stirred overnight. The reaction was loadedonto silica gel and eluted using a gradient of 0.25% to 2.0%methanol/dichloromethane to provide the title compound.

Example 7E3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(5,6-difluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid

To a solution of EXAMPLE 7D (0.085 g) in dichloromethane (0.5 mL) wasadded TFA (0.5 mL) and the reaction was stirred overnight. The reactionmixture was concentrated and dried to provide the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 12.98 (s, 1H), 8.20 (dd, 1H),7.93-7.83 (m, 2H), 7.70 (d, 1H), 7.58 (dd, 2H), 7.47-7.19 (m, 7H), 6.94(d, 1H), 5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).

Example 86-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 8A1-(4-fluorophenethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(2-bromoethyl)-4-fluorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 8B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-fluorophenethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 8A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 8C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(4-fluorophenyl)ethyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

To EXAMPLE 8B (0.040 g) in dichloromethane (1 mL) was added TFA (1 mL)and the reaction stirred overnight. The reaction was concentrated,dissolved in dichloromethane and loaded onto silica gel and eluted usinga gradient of 0.5% to 5% methanol/dichloromethane to provide the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.04 (s, 1H), 12.84(s, 1H), 8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (t, 2H),7.54-7.32 (m, 5H), 7.22-7.14 (m, 2H), 7.11-7.01 (m, 2H), 6.93 (d, 1H),4.94 (s, 2H), 4.30 (t, 2H), 3.08 (t, 2H), 3.08 (t, 2H), 3.00 (t, 2H).

Example 96-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 9A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

The title compound was prepared by substituting EXAMPLE 1D for EXAMPLE4C in EXAMPLE 6A.

Example 9B tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole andEXAMPLE 9A for EXAMPLE 1D in EXAMPLE 1E.

Example 9C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

A solution of EXAMPLE 9B (0.178 g), 1-(bromomethyl)-3-chlorobenzene(0.080 g) and cesium carbonate (0.170 g) was stirred together inN,N-dimethylformamide (2 mL) at room temperature. After 3 hours, thereaction was diluted with ethyl acetate (25 mL) and washed with water(20 mL), brine (20 mL), dried over magnesium sulfate, filtered, andconcentrated. The residue was dissolved in dichloromethane (1 mL) andtreated with TFA (1 mL) and stirred overnight. The mixture wasconcentrated, dissolved in dichloromethane and loaded onto silica geland eluted using a gradient of 0.5% to 4% methanol/dichloromethane toprovide the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.84 (s, 1H), 8.04 (dd, 1H), 7.95 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H),7.60 (dd, 2H), 7.53-7.28 (m, 7H), 7.22-7.16 (m, 1H), 6.95 (d, 1H), 5.35(s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 103-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid Example 10A tert-butyl3-(1-benzyl-1H-pyrazol-4-yl)-6-(8-(6-fluorobenzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared according to the procedure in EXAMPLE 7Dby substituting 5,6-difluorobenzo[d]thiazol-2-amine with6-fluorobenzo[d}thiazol-2-amine.

Example 10B3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-fluoro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid

The title compound was prepared according to the procedure in EXAMPLE 7Eby substituting EXAMPLE 7D with EXAMPLE 100A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.87 (s, 1H), 7.95 (dd, 1H), 7.91 (s, 1H),7.80 (dd, 1H), 7.70 (d, 1H), 7.59 (m, 2H), 7.32 (m, 9H), 6.94 (d, 1H),5.32 (s, 2H), 4.93 (s, 2H), 3.86 (t, 2H), 3.00 (t, 2H).

Example 113-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid Example 11A tert-butyl3-(1-benzyl-1H-pyrazol-4-yl)-6-(8-(6-methoxybenzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared according to the procedure in EXAMPLE 7Dby substituting 5,6-difluorobenzo[d]thiazol-2-amine with6-methoxybenzo[d]thiazol-2-amine.

Example 11B3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(6-methoxy-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid

The title compound was prepared according to the procedure in EXAMPLE 7Eby substituting EXAMPLE 7D with EXAMPLE 1A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.72 (s, 1H), 7.92 (s, 1H), 7.70 (dd, 2H),7.62 (d, 1H), 7.58 (m, 2H), 7.32 (m, 8H), 7.07 (dd, 1H), 6.94 (d, 1H),5.32 (s, 2H), 4.93 (s, 2H), 3.85 (m, 5H), 2.99 (t, 2H).

Example 126-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 12A1-benzyl-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolefor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole andbenzyl bromide for EXAMPLE 4A in EXAMPLE 4B.

Example 12B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 12A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 12C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 12B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.44-7.49 (m, 3H),7.31-7.39 (m, 4H), 7.27 (d, 1H), 7.10 (d, 2H), 6.96 (d, 1H), 5.23 (s,1H), 4.97 (s, 2H), 3.90 (t, 2H), 3.02 (t, 2H), 1.97 (s, 3H), 1.95 (s,3H).

Example 136-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 13A1-(3-methylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 3-methylbenzyl bromidefor EXAMPLE 4A in EXAMPLE 4B.

Example 13B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 13A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 13C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 13B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.90 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 760-7.83(m, 3H), 7.56 (s, 1H), 7.34-7.50 (m, 5H), 7.22 (t, 1H), 7.02-7.10 (m,3H), 6.94 (d, 1H), 5.27 (s, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.00 (t,2H), 2.27 (s, 3H).

Example 146-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 14A1-(3-methoxybenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 3-methoxylbenzyl bromidefor EXAMPLE 4A in EXAMPLE 4B.

Example 14B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 14A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 14C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 14B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 761 (d,1H), 7.57 (s, 1H), 7.52-7.50 (m, 2H), 7.34-7.38 (m, 2H), 7.32-7.27 (m,1H), 6.94 (d, 1H), 6.84-6.86 (m, 1H), 6.79-6.80 (m, 2H), 5.29 (s, 2H),4.94 (s, 2H), 3.88 (t, 2H), 3.71 (s, 3H), 3.00 (t, 2H).

Example 156-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 15A

1-(4-chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-4-chlorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 15B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

A solution of EXAMPLE 1D (0.205 g), EXAMPLE 15A (0.165 g), cesiumfluoride (0.197 g) and tetrakis(triphenylphosphine)palladium(0) (0.030g) were stirred together in 1,2-dimethoxyethane (1 mL) and methanol (0.5mL) and heated in a Biotage Initiator microwave reactor at 120° C. for30 minutes. The reaction was concentrated, loaded onto silica gel andeluted using a gradient of 0.5% to 2.5% methanol/dichloromethane to givethe corresponding ester which was dissolved in dichloromethane (1 mL)and treated with TFA (1 mL). After stirring overnight the reaction wasconcentrated, loaded onto silica gel and eluted using a gradient of 0.5%to 2.5% methanol/dichloromethane to provide the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 2H), 8.04 (dd, 1H), 7.92(d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d, 1H), 7.58 (d, 1H),7.52-7.31 (m, 6H), 7.29-7.22 (m, 2H), 6.94 (d, 1H), 5.33 (s, 2H), 4.94(s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 166-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 16A 1-(benzyloxy)-3-(bromomethyl)benzene

The title compound was prepared by substituting(3-(benzyloxy)phenyl)methanol for (4-(benzyloxy)phenyl)methanol inEXAMPLE 4A.

Example 16B1-(3-(benzyloxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 16A for EXAMPLE4A in EXAMPLE 4B.

Example 16C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 16B for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 16D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 16C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.91 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 761 (d,1H), 7.57 (s, 1H), 7.32-7.51 (m, 9H), 7.06 (d, 2H), 6.92-6.96 (m, 2H),6.80 (d, 1H), 6.84-6.86 (m, 1H), 6.79-6.80 (m, 2H), 5.29 (s, 2H), 5.07(s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 176-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 16D for EXAMPLE4C in EXAMPLE 4D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 9.41 (s, 1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.71 (d,1H), 761 (d, 1H), 7.57 (s, 1H), 7.42-7.50 (m, 2H), 7.34-7.38 (m, 2H),7.11 (t, 1H), 6.94 (d, 1H), 6.62-6.67 (m, 2H), 5.23 (s, 2H), 4.94 (s,2H), 3.86 (t, 2H), 3.00 (t, 2H).

Example 186-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 18A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 16C for EXAMPLE4C in EXAMPLE 6A.

Example 18B tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-hydroxybenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 18A for EXAMPLE4C in EXAMPLE 4D.

Example 18C tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 18B for EXAMPLE6B in EXAMPLE 6C.

Example 18D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 18(C for EXAMPLE6C in EXAMPLE 6D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 9.55 (s, 1H), 8.04 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H), 7.71 (d,1H), 762 (d, 1H), 7.59 (s, 1H), 7.42-7.50 (m, 2H), 7.28-7.38 (m, 3H),6.89-6.96 (m, 3H), 6.85 (s, 3H), 5.31 (s, 2H), 4.95 (s, 2H), 4.25-4.28(m, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.84 (s, 6H).

Example 196-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 19A1-benzyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzylbromide for EXAMPLE 4A in EXAMPLE 4B.

Example 19B

The title compound was prepared by substituting EXAMPLE 19A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 19C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 19B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.66 (s, 1H), 762 (d, 1H), 7.54 (d,1H), 7.43-7.50 (m, 2H), 7.21-7.38 (m, 7H), 6.94 (d, 1H), 5.32 (s, 2H),4.95 (s, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.03 (s, 3H).

Example 206-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 20A1-benzyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared as a minor regioisomer using theprocedure described in EXAMPLE 19A.

Example 20B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 20A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 20C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 20B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.43-7.49(m, 2H), 7.31-7.38 (m, 5H), 7.25-7.28 (m, 1H), 7.11 (d, 2H), 6.95 (d,1H), 5.32 (s, 2H), 4.96 (s, 2H), 3.88 (t, 2H), 3.01 (t, 2H), 2.08 (s,3H).

Example 213-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(7-chloro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid Example 21A tert-butyl3-(1-benzyl-1H-pyrazol-4-yl)-6-(8-(7-chlorobenzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared according to the procedure in EXAMPLE 7Dby substituting 5,6-difluorobenzo[d]thiazol-2-amine with4-chlorobenzo[d}thiazol-2-amine.

Example 21B3-(1-benzyl-1H-pyrazol-4-yl)-6-{8-[(7-chloro-1,3-benzothiazol-2-yl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}pyridine-2-carboxylicacid

The title compound was prepared according to the procedure in EXAMPLE 7Eby substituting EXAMPLE 7D with EXAMPLE 21A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 13.07 (s, 1H), 7.91 (s, 1H), 7.79 (d, 1H),7.71 (d, 2H), 7.63 (d, 1H), 7.57 (s, 1H), 7.37 (m, 8H), 6.96 (d, 2H),5.32 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 226-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 22A2-(pyrrolidin-1-yl)-6-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridine

The title compound was prepared by substituting2-(bromomethyl)-6-(pyrrolidin-1-yl)pyridine for EXAMPLE 4A in EXAMPLE4B.

Example 22B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)picolinate

EXAMPLE 1D (0.100 g), EXAMPLE 22A (0.094 g),tetrakis(triphenylphosphine)palladium(0) (10.22 mg) and cesium carbonate(0.173 g) were stirred together in N,N-dimethylformamide (0.6 mL),dioxane (0.4 mL), and water (0.2 mL) and the reaction degassed withnitrogen and heated at 100° C. for 1 hour. The reaction was diluted withethyl acetate (25 mL) and washed with water (25 mL) and brine (25 mL),dried over magnesium sulfate, filtered, and concentrated. Silica gelchromatography eluting with methanol/dichloromethane provided the titlecompound.

Example 22C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 22B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.65-7.32(m, 7H), 6.95 (1H), 6.52 (d, 1H), 6.21 (d, 1H), 5.30 (s, 2H), 4.95 (s,2H), 3.87 (t, 2H), 3.40 (tt, 4H), 3.00 (t, 2H), 1.94 (t, 4H).

Example 236-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 23A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-phenyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 23B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 23B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.57 (s, 1H), 8.05 (d, 1H), 7.79-7.83 (m, 5H), 7.62 (d, 1H),7.43-7.53 (m, 5H), 7.30-7.39 (m, 3H), 7.01 (d, 1H), 4.98 (s, 2H), 3.90(t, 2H), 3.02 (t, 2H).

Example 246-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 24A3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)benzonitrile

The title compound was prepared by substituting3-(bromomethyl)benzonitrile for EXAMPLE 4A in EXAMPLE 4B.

Example 24B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 24A for EXAMPLE22A in EXAMPLE 22B.

Example 24C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-cyanobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 24B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.98 (d,2H), 8.07-8.01 (m, 1H), 7.97 (s, 1H), 7.82-7.68 (m, 4H), 7.65-7.53 (m,4H), 7.51-7.31 (m, 4H), 6.95 (d, 1H), 5.41 (s, 2H), 4.95 (s, 2H), 3.87(t, 2H), 3.00 (t, 2H).

Example 256-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 25A1-(2-chlorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-2-chlorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 25B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-chlorobenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 25A for EXAMPLE22A in EXAMPLE 22B.

Example 25C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-chlorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 25B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.04 (d, 1H), 7.93 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d,2H), 7.52-7.27 (m, 7H), 7.01 (dd, 1H), 6.95 (d, 1H), 5.43 (s, 2H), 4.95(s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 266-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 26A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)pyridinefor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 1E.

Example 26B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 26A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.97 (s, 1H), 7.82-7.86 (m, 1H), 7.79(d, 1H), 7.73 (d, 1H), 7.61-7.62 (m, 2H), 7.42-7.50 (m, 2H), 7.34-7.39(m, 3H), 7.11 (d, 1H), 6.95 (d, 1H), 5.45 (s, 2H), 4.95 (s, 2H), 3.87(t, 2H), 3.00 (t, 2H).

Example 276-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-cyano-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 27A1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carbonitrile

The title compound was prepared by substituting benzyl bromide forEXAMPLE 4A and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-3-carbonitrilefor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 4B.

Example 27B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-3-cyano-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 27A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 27C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-cyano-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 27B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.15 (s, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.62 (d,1H), 7.43-7.49 (m, 2H), 7.29-7.39 (m, 7H), 7.05 (d, 1H), 5.45 (s, 2H),5.01 (s, 2H), 3.92 (t, 2H), 3.02 (t, 2H).

Example 286-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 28A1-(naphthalen-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting2-(bromomethyl)naphthalene for EXAMPLE 4A in EXAMPLE 4B.

Example 28B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 28A for EXAMPLE22A in EXAMPLE 22B.

Example 28C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(naphthalen-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 28B for EXAMPLEE in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.83 (brs, 1H), 8.04 (d, 1H), 7.98 (s, 1H), 7.88 (m, 3H), 7.78 (m, 2H), 7.72 (d,1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.36 (m, 4H), 6.94 (d, 1H), 5.50 (s,2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 296-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 29A3-methyl-5-(3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)phenyl)-1,2,4-oxadiazole

The title compound was prepared by substituting5-(3-(bromomethyl)phenyl)-3-methyl-1,2,4-oxadiazole for EXAMPLE 4A inEXAMPLE 4B.

Example 29B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 29A for EXAMPLE22A in EXAMPLE 22B.

Example 29C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 29B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (m,2H), 8.08-7.97 (m, 4H), 7.79 (d, 1H), 7.72 (d, 1H), 7.65-7.52 (m, 4H),7.51-7.31 (m, 4H), 6.95 (d, 1H), 5.47 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H), 2.40 (s, 3H).

Example 306-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 30A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

A mixture of EXAMPLE 1D (1.2 g), 1.0 M4,4,5,5-tetramethyl-1,3,2-dioxaborolane in tetrahydrofuran (4.24 mL),triethylamine (0.92 mL), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (0.087 g) in CH₃CN (15 mL) was heated at 100° C. in aBiotage Initiator microwave reactor for 30 minutes. After cooling, thereaction mixture was partitioned between water and ethyl acetate. Theorganic layer was extracted with additional ethyl acetate twice. Thecombined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified by flash columnchromatography on silica gel to provide the title compound.

Example 30B ethyl 1-benzyl-4-bromo-5-methyl-1H-pyrazole-3-carboxylate

The title compound was prepared by substituting (1-bromomethyl)benzenefor EXAMPLE 4A and methyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE4B.

Example 30C (1-benzyl-4-bromo-5-methyl-1H-pyrazol-3-yl)methanol

EXAMPLE 30B (0.281 g) in tetrahydrofuran (10 mL) was treated with 1.0 MLiAlH₄ in tetrahydrofuran (1.0 mL) at 0° C. After the reaction wascomplete, the reaction mixture was quenched by 1.0 N aqueous HCl. It wasthen partitioned between water and ethyl acetate. The organic layer wasextracted with additional ethyl acetate twice. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash column chromatography onsilica gel to provide the title compound.

Example 30D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 30A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole andEXAMPLE 30C for EXAMPLE 1D in EXAMPLE 1E.

Example 30E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(hydroxymethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 30D for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56 (d, 1H), 7.43-7.49(m, 2H), 7.31-7.39 (m, 7H), 7.24-7.28 (m, 1H), 7.11 (d, 2H), 6.98 (d,1H), 5.28 (s, 2H), 4.97 (s, 2H), 4.20 (s, 2H), 3.91 (t, 2H), 3.02 (t,2H), 1.97 (s, 3H).

Example 316-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 31A 1-(benzyloxy)-2-(bromomethyl)benzene

The title compound was prepared by substituting(2-(benzyloxy)phenyl)methanol for (4-(benzyloxy)phenyl)methanol inEXAMPLE 4A.

Example 31B1-(2-(benzyloxy)benzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 31A for EXAMPLE4A in EXAMPLE 4B.

Example 31C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 31B for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 31D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(benzyloxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 31C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79-7.80 (m, 2H), 7.61-7.63 (m, 2H), 7.56 (s, 1H),7.40-7.50 (m, 4H), 7.25-7.38 (m, 6H), 7.09 (d, 2H), 6.98-7.00 (m, 1H),6.89-9.94 (m, 2H), 5.32 (s, 2H), 5.17 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 2.98 (t, 2H).

Example 326-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid and6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-methyl-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 32A2-((5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)-6-(pyrrolidin-1-yl)pyridineand2-((3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)-6-(pyrrolidin-1-yl)pyridine

The title compounds were prepared by substituting2-(bromomethyl)-6-(pyrrolidin-1-yl)pyridine for EXAMPLE 4A and3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE4B. The title compounds were isolated as a 2:1 mixture of theregioisomeric pyrazole isomers, and were used in the next step withoutfurther purification.

Example 32B tert-butyl6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine-2-carboxylateand tert-butyl6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-methyl-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine-2-carboxylate

The titles compound were prepared by substituting EXAMPLE 32A forEXAMPLE 22A in EXAMPLE 228. The title compounds were isolated as a 2:1mixture of the regioisomeric pyrazole isomers.

Example 32C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[6-(pyrrolidin-1-yl)pyridin-2-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid and6-(8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-methyl-1-((6-(pyrrolidin-1-yl)pyridin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compounds were prepared by substituting EXAMPLE 32B forEXAMPLE 8B in EXAMPLE 8C. The title compounds were isolated as a 2:1mixture of the regioisomeric pyrazole isomers. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H),7.62 (d, 1H), 7.57-7.29 (m, 7H), 6.97 (d, 1H), 6.42 (m, 1H), 6.02 (d,1H), 4.96 (s, 2H), 3.89 (m, 2H), 3.39 (d, 4H), 3.17 (s, 2H), 2.99 (m,2H), 2.17 (s, 3H), 1.93 (m, 4H).

Isomeric Pyrazole: ¹H NMR (300 MHz, DMSO) δ 12.86 (s, 2H), 8.04 (d, 1H),7.79 (d, 1H), 7.69 (s, 1H), 7.62 (d, 1H), 7.57-7.29 (m, 6H), 6.97 (d,1H), 6.42 (m, 1H), 6.02 (d, 1H), 4.96 (s, 2H), 3.89 (m, 2H), 3.39 (d,4H), 3.17 (s, 2H), 2.99 (m, 2H), 2.04 (s, 3H), 1.93 (m, 4H).

Example 336-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 33A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 30A for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and EXAMPLE30B for EXAMPLE 1D in EXAMPLE 1E.

Example 33B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-3-(ethoxycarbonyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 33A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.35 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43-7.49 (m, 3H),7.34-7.38 (m, 4H), 7.30 (d, 1H), 7.12 (d, 2H), 6.99 (d, 1H), 5.44 (s,2H), 4.99 (s, 2H), 4.01-4.06 (m, 2H), 3.93-3.96 (m, 2H), 3.02 (t, 2H),2.00 (s, 3H), 1.05 (t, 3H).

Example 346-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 34AN,N-dimethyl-3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)aniline

To a solution of (3-(dimethylamino)phenyl)methanol (0.100 g),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.167 g)and cyanomethylenetributylphosphorane (0.208 g) were added and stirredtogether in toluene (1 mL) at room temperature. After stirring overnightthe reaction was loaded directly onto silica gel and eluted using agradient of 5% to 35% ethyl acetate/hexanes to provide the titlecompound.

Example 34B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 34A for EXAMPLE22A in EXAMPLE 22B.

Example 34C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 34B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (dd, 1H), 7.88 (d, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d,1H), 7.56 (d, 1H), 7.53-7.44 (m, 1H), 7.44-7.31 (m, 3H), 7.20-7.10 (m,1H), 6.94 (d, 1H), 6.67 (d, 2H), 6.53 (t, 1H), 5.24 (s, 2H), 4.94 (s,2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.87 (s, 6H).

Example 356-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-3-carboxy-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

EXAMPLE 33B (0.05 g) in dioxane (2 mL) and methanol (0.5 mL) was treatedwith 2.0N aqueous NaOH (1 mL). The reaction mixture was heated at 90° C.for 1 hours. The solvents were removed under reduced pressure, and theresidue was purified by reverse phase Prep HPLC using Gilson system. Thedesired fractions were combined and freeze-dried to provide the titlecompound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.44-7.49 (m, 3H), 7.34-7.39(m, 4H), 7.29 (d, 1H), 7.13 (d, 2H), 7.00 (d, 1H), 5.41 (s, 2H), 4.98(s, 2H), 3.87 (t, 2H) 3.03 (t, 2H), 1.98 (s, 3H).

Example 366-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-hydroxybenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 31D for EXAMPLE4C in EXAMPLE 4D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 9.75 (s, 1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.70 (d,1H), 761 (d, 1H), 7.55 (s, 1H), 7.46-7.50 (m, 1H), 7.42-7.43 (m, 1H),7.34-7.37 (m, 2H), 7.09-7.13 (m, 1H), 6.90-6.94 (m, 2H), 6.82-6.64 (m,1H), 6.72-6.76 (m, 1H), 5.23 (s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99(t, 2H).

Example 376-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 37A1-(2,3-dihydro-1H-inden-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting2,3-dihydro-1H-inden-1-ol for (3-(dimethylamino)phenyl)methanol inEXAMPLE 34A.

Example 37B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 37A for EXAMPLE22A in EXAMPLE 22B.

Example 37C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-dihydro-1H-inden-1-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 37B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,2H), 8.04 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d,1H), 7.56 (d, 1H), 7.53-7.44 (m, 1H), 7.44-7.31 (m, 4H), 7.30-7.23 (m,1H), 7.17 (t, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 5.95-5.82 (m, 1H), 4.94(s, 2H), 3.86 (t, 2H), 3.21-3.06 (m, 1H), 3.06-2.84 (m, 3H), 2.68-2.54(m, 1H), 2.40 (m, 1H).

Example 386-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 38A1-phenethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 2-phenylethanol for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 38Btert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 38A for EXAMPLE22A in EXAMPLE 22B.

Example 38C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 38B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (brs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.73 (s, 1H), 7.64 (d, 1H), 7.61 (d,1H), 7.54 (s, 1H), 7.48 (m, 1H), 7.42 (d, 1H), 7.36 (t, 2H), 7.26 (m,2H), 7.18 (m, 2H), 6.94 (d, 1H), 4.94 (s, 2H), 4.32 (t, 2H), 3.86 (t,2H), 3.09 (t, 2H), 3.00 (t, 2H).

Example 396-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,4-dihydro-2H-chromen-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 39A1-(chroman-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting chroman-4-ol for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 39B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(chroman-4-yl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 39A for EXAMPLE22A in EXAMPLE 22B.

Example 39C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,4-dihydro-2H-chromen-4-yl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 39B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,2H), 8.08-7.99 (m, 1H), 7.80 (t, 2H), 7.72 (d, 1H), 7.66-7.57 (m, 2H),7.52-7.44 (m, 1H), 7.44-7.31 (m, 3H), 7.19 (m, 1H), 6.93 (d, 1H),6.90-6.78 (m, 3H), 5.65 (t, 1H), 4.94 (s, 2H), 4.38-4.15 (m, 2H), 3.86(t, 2H), 3.00 (t, 2H), 2.41-2.18 (m, 2H).

Example 406-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 40A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(benzyloxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 31C. for EXAMPLE4C in EXAMPLE 6A.

Example 40B tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-hydroxybenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 40A for EXAMPLE4C in EXAMPLE 4D.

Example 40C tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(2-(dimethylamino)ethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE6B in EXAMPLE 6C.

Example 40D66-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 40C for EXAMPLE6C in EXAMPLE 6D. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 9.64 (s, 1H), 8.04 (d, 1H), 7.86 (s, 1H), 7.80 (d, 1H), 7.71 (d,1H), 761-7.63 (m, 2H), 7.46-7.50 (m, 2H), 7.42-7.44 (m, 1H), 7.31-7.38(m, 3H), 7.10 (dd, 1H), 7.07 (d, 1H), 6.94-6.99 (m, 2H), 5.37 (s, 2H),4.35-4.36 (m, 2H), 3.86 (t, 2H), 3.57 (m, 1H), 3.00 (t, 2H), 2.90 (s,6H).

Example 416-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 41A1-(2-fluorobenzyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and2-fluorobenzyl bromide for EXAMPLE 4A in EXAMPLE 4B.

Example 41B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 41A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 41C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-fluorobenzyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 41B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.43-7.49(m, 2H), 7.32-7.38 (m, 4H), 7.20-7.25 (m, 1H), 7.13-7.17 (m, 1H), 6.96(d, 1H), 6.88-6.93 (m, 1H), 5.35 (s, 2H), 4.96 (s, 2H), 3.88-3.91 (m,2H), 3.01 (t, 2H), 2.12 (s, 3H).

Example 426-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 42A1-(cyclohexylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting (bromomethyl)cyclohexanefor EXAMPLE 4A in EXAMPLE 4B.

Example 42B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(cyclohexylmethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 42A for EXAMPLE22A in EXAMPLE 22B.

Example 42C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 42B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.68 (s, 1H), 7.61 (d,1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.42 (d, 1H), 7.36 (s, 2H), 6.94(d, 1H), 4.94 (s, 2H), 3.91 (d, 2H), 3.86 (t, 2H), 3.00 (t, 2H), 1.76(m, 1H), 1.70-1.56 (m, 3H), 1.51 (d, 2H), 1.26-1.02 (m, 3H), 0.92 (m,2H).

Example 436-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 43A1-(cyclohexylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and(bromomethyl)cyclohexane for EXAMPLE 4A in EXAMPLE 4B.

Example 43B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 43A for EXAMPLE22A in EXAMPLE 22B.

Example 43C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 43B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (s, 3H), 7.39-7.31(m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.86 (s, 4H), 3.01(t, 2H), 2.10 (s, 3H), 1.88-1.71 (m, 1H), 1.65 (s, 3H), 1.53 (d, 2H),1.26-1.05 (m, 3H), 0.98 (t, 2H).

Example 446-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-{[3-(dimethylamino)propyl]amino}-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

N,N-Dimethylpropane-1,3-diamine (50 mg) and EXAMPLE 45B (90 mg) intetrahydrofuran (10 mL) were treated with triethylamine (0.1 mL) at 70°C. for 2 days. The reaction mixture was concentrated and the cruderesidue was dissolved in a mixture of dichloromethane (5 mL) and TFA (5mL). The resulting mixture was stirred for 12 hours and concentrated.The residue was purified by reverse phase chromatography, eluting with agradient of 40%-80% acetonitrile in 0.1% TFA water over 40 minutes toprovide the title compound as a TFA salt. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ ppm 13.08 (s, 1H), 12.85 (s, 1H), 9.28 (s, 1H),8.23 (t, 1H), 8.11 (d, 1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.79 (d, 1H),7.69 (d, 1H), 7.61 (d, 1H), 7.57 (s, 1H), 7.45-7.52 (m, 2H), 7.40-7.44(m, 1H), 7.36 (t, 2H), 7.07 (d, 1H), 6.94 (d, 1H), 5.25 (s, 2H), 4.94(s, 2H), 3.86 (t, 2H), 3.05-3.15 (m, 2H), 3.00 (t, 2H), 2.76 (d, 6H),1.86-1.98 (m, 2H).

Example 456-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 45A1-(4-fluoro-3-nitrobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting4-(bromomethyl)-1-fluoro-2-nitrobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 45B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 45A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 45C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-fluoro-3-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 45B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.10 (dd, 1H), 8.04 (d, 1H), 7.99 (s, 1H), 7.79 (d, 1H), 7.65-7.73(m, 2H), 7.54-7.64 (m, 3H), 7.45-7.51 (m, 1H), 7.40-7.45 (m, 1H), 7.36(t, 2H), 6.95 (d, 1H), 5.45 (s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00(t, 2H).

Example 466-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 46A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(2-morpholinoethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE6B and 2-morpholinoethanol for 2-(dimethylamino)ethanol in EXAMPLE 6C.

Example 46B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 46A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.80 (d, 1H), 7.72 (d, 1H), 7.62 (d,1H), 7.59 (s, 1H), 7.46-7.50 (m, 1H), 7.42-7.44 (m, 1H), 7.31-7.38 (m,3H), 7.07-7.09 (m, 2H), 6.93-6.99 (m, 2H), 5.35 (s, 2H), 4.95 (s, 2H),4.38-4.40 (m, 2H), 3.86 (t, 2H), 3.60-3.63 (m, 2H), 3.00 (t, 2H).

Example 476-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 47A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(3-(dimethylamino)propoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE6B and 3-(dimethylamino)propan-1-ol for 2-(dimethylamino)ethanol inEXAMPLE 6C.

Example 47B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 47A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 9.38 (s, 1H), 8.04 (d, 1H), 7.82 (s, 1H), 7.80 (d, 1H), 7.71 (d,1H), 7.62 (d, 1H), 7.59 (s, 1H), 7.46-7.50 (m, 1H), 7.42-7.44 (m, 1H),7.35-7.38 (m, 2H), 7.29-7.32 (m, 1H), 7.06 (dd, 1H), 7.01 (d, 1H),6.92-6.95 (m, 2H), 5.30 (s, 2H), 4.94 (s, 2H), 4.08 (t, 2H), 3.86 (t,2H), 3.21-3.25 (m, 2H), 3.00 (t, 2H), 2.80 (s, 6H), 2.09-2.14 (m, 2H).

Example 486-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(pyridin-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 48A tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(pyridin-4-ylmethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 40B for EXAMPLE6B and pyridin-4-ylmethanol for 2-(dimethylamino)ethanol in EXAMPLE 6C.

Example 48B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(pyridin-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 48A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 9.38 (s, 1H), 8.71 (d, 2H), 8.04 (d, 1H), 7.84 (s, 1H), 7.79 (d,1H), 7.72 (d, 2H), 7.67 (d, 1H), 7.61 (d, 1H), 7.59 (s, 1H), 7.46-7.50(m, 1H), 7.42-7.43 (m, 1H), 7.34-7.38 (m, 2H), 7.27-7.32 (m, 1H),7.04-7.09 (m, 2H), 6.96-6.98 (m, 1H), 6.93 (d, 1H), 5.41 (s, 2H), 5.38(s, 2H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H).

Example 496-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 49A1-(2-(benzyloxy)benzyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and EXAMPLE31A for EXAMPLE 4A in EXAMPLE 4B. The desired product was isolated viaPrep HPLC using a Gilson system.

Example 49B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(benzyloxy)benzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 49A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 49C tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(benzyloxy)benzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 49B for EXAMPLE4C in EXAMPLE 6A.

Example 49D tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-hydroxybenzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 49C for EXAMPLE4C in EXAMPLE 4D.

Example 49E tert-butyl6-(8-(benzo[d]thiazol-2-yl((2-(trimethylsilyl)ethoxy)methyl)carbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(2-(dimethylamino)ethoxy)benzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 49D for EXAMPLE6B in EXAMPLE 6C.

Example 49F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[2-(dimethylamino)ethoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 49E for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 9.67 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.55-7.64 (m, 2H), 7.52(d, 1H), 7.43-7.50 (m, 3H), 7.29-7.39 (m, 3H), 7.07 (d, 1H), 6.93-6.98(m, 2H), 6.77 (dd, 1H), 5.34 (s, 2H), 4.96 (s, 2H), 4.36-4.39 (m, 2H),3.89 (t, 2H), 3.58 (d, 2H), 3.01 (t, 2H), 2.93 (d, 6H), 2.09 (s, 3H).

Example 506-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 50A1-((tetrahydro-2H-pyran-4-yl)methyl)-4-(4,4,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-4-yl)methanol for (3-(dimethylamino)phenyl)methanolin EXAMPLE 34A.

Example 50B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 50A for EXAMPLE22A in EXAMPLE 22B.

Example 50C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 50B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.06-8.01 (m, 1H), 7.79 (d, 1H), 7.76 (d, 1H), 7.69 (d, 1H), 7.61(d, 1H), 7.53 (d, 1H), 7.51-7.44 (m, 1H), 7.42 (d, 1H), 7.39-7.32 (m,2H), 6.94 (d, 1H), 4.94 (s, 2H), 3.99 (d, 2H), 3.83 (dt, 4H), 3.24 (td,2H), 3.00 (t, 2H), 2.01 (ddd, 1H), 1.46-1.31 (m, 2H), 1.22 (dd, 2H).

Example 516-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)prop-1-yn-1-yl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 51A1-(2-bromobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-bromo-2-(bromomethyl)benzene for EXAMPLE 4A in EXAMPLE 4B.

Example 51N,N-dimethyl-3-(2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)phenyl)prop-2-yn-1-amine

EXAMPLE 51A (0.11 g), N,N-dimethylprop-2-yn-1-amine (0.1 g),tetrakis(triphenylphosphine)palladium(0) (0.05 g), copper(I) iodide(0.01 g) and triethylamine (0.3 mL) were suspended inN,N-dimethylformamide (2 mL) in a 5 mL microwave tube. The mixture washeated at 110° C. in a microwave reactor (Biotage, Iniator) for 30minutes. Additional tetrakis(triphenylphosphine)palladium(0) (0.05 g)was added, and the mixture was heated in a microwave reactor (Biotage,Iniator) at 120° C. for 1 hour. The crude product was filtered andpurified by PrepHPLC (Gilson, C18, Phenomenex®, 250×21.2 mm column) andwas eluted with 30-100% CH₃CN/water with 0.1% TFA to provide the titlecompound.

Example 51C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(3-(dimethylamino)prop-1-ynyl)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 51B for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 51D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-(dimethylamino)prop-1-yn-1-yl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 51C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (m,1H), 8.04 (d, 1H), 7.92 (m, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.59 (m,3H), 7.41 (m, 7H), 7.12 (d, 1H), 6.94 (d, 1H), 5.50 (s, 2H), 4.95 (s,2H), 4.38 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.89 (s, 6H).

Example 526-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 52A1-(2,3-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-2,3-difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 52B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 52A for EXAMPLE22A in EXAMPLE 22B.

Example 52C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,3-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 52B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (brs, 1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d,1H), 7.59 (s, 1H), 7.48 (t, 1H), 7.42 (d, 1H), 7.36 (m, 3H), 7.19 (m,1H), 7.01 (m, 1H), 6.94 (d, 1H), 5.44 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H).

Example 536-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 53A1-(3,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-3,5-difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 53B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 53A for EXAMPLE22A in EXAMPLE 22B.

Example 53C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 53B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 1H), 8.04 (d, 1H), 7.96 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.62 (d,1H), 7.61 (s, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 7.36 (t, 2H), 7.17 (m,1H), 6.94 (d, 1H), 6.92 (m, 2H), 5.38 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H).

Example 546-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 54A1-(2,5-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-2,5-difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 54B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 54A for EXAMPLE22A in EXAMPLE 22B.

Example 54C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,5-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 54B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (brs, 1H), 8.04 (d, 1H), 7.94 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d,1H), 7.60 (s, 1H), 7.48 (t, 1H), 7.43 (d, 1H), 7.36 (t, 2H), 7.29 (m,1H), 7.22 (m, 1H), 7.00 (m, 1H), 6.95 (d, 1H), 5.39 (s, 2H), 4.95 (s,2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 556-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 55A1-(2,6-difluorobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-2,6-difluorobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 55B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 55A for EXAMPLE22A in EXAMPLE 22B.

Example 55C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,6-difluorobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 55B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 1H), 8.04 (d, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d,1H), 7.53 (s, 1H), 7.48 (m, 2H), 7.42 (d, 1H), 7.36 (t, 2H), 7.14 (t,2H), 6.93 (d, 1H), 5.37 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t,2H).

Example 566-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 56A1-((tetrahydro-2H-pyran-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-3-yl)methanol for (3-(dimethylamino)phenyl)methanolin EXAMPLE 34A.

Example 56B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 56A for EXAMPLE22A in EXAMPLE 22B.

Example 56C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 56B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.07-8.01 (m, 1H), 7.76 (d, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.53(d, 1H), 7.51-7.44 (m, 1H), 7.43 (d, 1H), 7.35 (dd, 3H), 6.94 (d, 1H),4.94 (s, 2H), 4.00 (dd, 2H), 3.87 (t, 2H), 3.75-3.64 (m, 1H), 3.60 (dd,1H), 3.38-3.26 (m, 1H), 3.14 (dd, 1H), 3.00 (t, 2H), 2.02 (s, 1H), 1.61(dd, 2H), 1.52-1.34 (m, 1H), 1.21 (d, 1H).

Example 576-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 57A1-(2-nitrobenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-2-nitrobenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 57B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-nitrobenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 57A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 57C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-nitrobenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 57B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.09 (dd, 1H), 8.03 (d, 1H), 7.95 (s, 1H), 7.75 (m, 3H), 7.47 (m,8H), 6.96 (d, 1H), 6.87 (dd, 1H), 5.72 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H).

Example 586-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 58A1-Biphenyl-3-ylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 3-(bromomethyl)biphenylfor EXAMPLE 4A in EXAMPLE 4B.

Example 58B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

EXAMPLE 58A (76 mg) and EXAMPLE 1D (100 mg) were added to 1,4-dioxane(1.5 mL). 2M aqueous sodium carbonate (0.265 mL) was added. The solutionwas degassed and flushed with nitrogen three times.Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (14 mg) was added. The solution was degassed andflushed with nitrogen and then heated at 70° C. for 16 hours. Thesolution was cooled, added to water, extracted with 50% ethyl acetate inhexanes, washed with brine, dried on anhydrous sodium sulfate, andconcentrated under vacuum. The crude material was purified on silica gelusing 30-50% ethyl acetate in hexanes.

Example 58C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 58B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(bs, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.80 (d, 1H), 7.72 (d, 1H),7.66-7.53 (m, 6H), 7.51-7.32 (m, 8H), 7.23 (d, 1H), 6.95 (d, 1H), 5.40(s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 596-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 59A1-neopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 2,2-dimethylpropan-1-olfor (3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 59B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-neopentyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 59A for EXAMPLE22A in EXAMPLE 22B.

Example 59C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2,2-dimethylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 59B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm13.08-12.70 (m, 1H), 8.04 (dd, 1H), 7.79 (d, 1H), 7.71 (dd, 2H),7.66-7.58 (m, 1H), 7.53 (d, 1H), 7.52-7.45 (m, 1H), 7.45-7.31 (m, 3H),6.94 (d, 1H), 4.94 (s, 2H), 3.94-3.79 (m, 4H), 3.00 (t, 2H), 0.89 (s,9H).

Example 606-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 60A1-(2-cyclohexylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting(2-bromoethyl)cyclohexane for EXAMPLE 4A in EXAMPLE 4B.

Example 60B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 60A for EXAMPLE22A in EXAMPLE 22B.

Example 60C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 60B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.87 (br s,1H), 8.04 (d, 1H), 7.80 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H), 7.61 (d,1H), 7.51 (s, 1H), 7.48 (m, 1H), 7.42 (d, 1H), 7.36 (t, 2H), 6.94 (d,1H), 4.95 (s, 2H), 4.10 (t, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 1.66 (m,7H), 1.15 (m, 4H), 0.90 (m, 2H).

Example 616-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 61A1-[3-(trifluoromethyl)benzyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-3-(trifluormethyl)benzene for EXAMPLE 4A in EXAMPLE 4B.

Example 61B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 61A for EXAMPLE22A in EXAMPLE 22B.

Example 61C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(trifluoromethyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 61B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 12.85 (br s,1H), 8.04 (d, 1H), 8.00 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d,1H), 7.61 (m, 4H), 7.48 (m, 3H), 7.36 (t, 2H), 6.94 (d, 1H), 5.45 (s,2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 626-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 62A1-Biphenyl-2-ylmethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting 2-(bromomethyl)biphenylfor EXAMPLE 4A in EXAMPLE 4B.

Example 62B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 62A for EXAMPLE58A in EXAMPLE 58B.

Example 62C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(biphenyl-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 62B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.68-7.65 (m, 2H), 7.72 (d, 1H),7.61 (d, 1H), 7.50-7.31 (m, 1H), 7.26 (dd, 1H), 7.07 (dd, 1H), 6.94 (d,1H), 5.26 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 636-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 63A 1-(cyclopentylmethyl)-1H-pyrazole

A flask was charged with pyrazole (380 mg), (bromomethyl)cyclopentane(968 mg), tetrabutylammonium bromide (18 mg), 50% aqueous NaOH (0.6 mL)and toluene (1.5 mL) and the mixture was heated to 110° C. for 4.5hours. The reaction mixture was cooled to room temperature andpartitioned between toluene (3×10 mL) and H₂O (10 mL). The extracts weredried (MgSO₄), filtered, and concentrated to give the title compound.

Example 63B 1-(cyclopentylmethyl)-5-methyl-1H-pyrazole

A solution of EXAMPLE 63A (727 mg) in tetrahydrofuran (10 mL) waschilled to −45° C. n-Butyllithium (2.3 M solution in hexanes, 2.52 mL)was added dropwise over 5 minutes. The reaction was stirred for 1.5hours, during which time the temperature increased to −20° C.Iodomethane (0.368 mL) was added dropwise over 3 minutes. The reactionwas stirred for 30 minutes between −20 and −15° C. Water (25 mL) wasadded and the mixture was extracted with ethyl acetate (3×25 mL). Theextracts were dried (Na₂SO₄), filtered, and concentrated to provide thetitle compound.

Example 63C 4-bromo-1-(cyclopentylmethyl)-5-methyl-1H-pyrazole

EXAMPLE 63B (570 mg) was dissolved in N,N-dimethylformamide (5 mL) andN-bromosuccinimide (649 mg) was added. The reaction was stirred at roomtemperature for 2.5 hours. 10% Aqueous Na₂S₂O₃ (10 mL) and water (20 mL)were added and the reaction was extracted with ethyl acetate (3×25 mL).The combined extracts were dried (Na₂SO₄), filtered, and concentrated.Silica gel chromatography (gradient from 0 to 10% ethyl acetate-hexanesover 25 minutes) provided the title compound.

Example 63D1-(cyclopentylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

EXAMPLE 63C (220 mg), bis(pinacolato)diboron (276 mg) and potassiumacetate (240 mg) were combined in N,N-dimethylformamide (3 mL) and themixture was degassed with N₂.[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (44 mg) wasadded, the reaction vessel was sealed, and the mixture was heated to 90°C. for 18 hours. The reaction mixture was partitioned between H₂O (15mL) and ethyl acetate, and the aqueous layer was extracted with ethylacetate (3×10 mL). The extracts were dried (Na₂SO₄), filtered, andconcentrated, and the residue was purified by flash chromatography(gradient from 0 to 10% ethyl acetate/hexanes) to provide the titlecompound.

Example 63E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 63D for EXAMPLE22A in EXAMPLE 22B.

Example 63F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclopentylmethyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 63E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.70-12.88 (m, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41-7.52(m, 3H), 7.32-7.39 (m, 2H), 7.25 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H),3.94 (d, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.28-2.38 (m, 1H), 2.12 (s,3H), 1.42-1.66 (m, 6H), 1.20-1.32 (m, 2H).

Example 646-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 64A3-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-ylmethyl]-benzaldehyde

The title compound was prepared by substituting3-(bromomethyl)benzaldehyde for EXAMPLE 4A in EXAMPLE 4B.

Example 64B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 64A for EXAMPLE58A in EXAMPLE 58B.

Example 64C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-formylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 64B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 9.98 (s, 1H), 8.04 (d, 1H), 7.98 (s, 1H), 7.87-7.78 (m, 3H),7.72 (d, 1H), 7.63-7.54 (m, 3H), 7.51-7.32 (m, 5H), 6.95 (d, 1H), 5.45(s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H).

Example 656-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 65A ethyl 2-(2-phenyl-1,3-dioxolan-2-yl)acetate

A solution of ethyl 3-oxo-3-phenylpropanoate (23.74 g) in toluene,ethyleneglycol (23.04 g), and p-toluenesulfonic acid (200 mg) in toluene(300 mL) was stirred under reflux with a Dean-Stark trap for 15 hours.The cooled mixture was poured onto saturated aqueous sodium bicarbonate(100 mL) and the organic layer was washed with water, brine and driedover Na₂SO₄. Filtration and evaporation of solvent provided the titlecompound which was used in the next reaction without furtherpurification.

Example 65B 2-(2-phenyl-1,3-dioxolan-2-yl)acetaldehyde

To a solution of EXAMPLE 65A (2.36 g) in toluene (30 mL) was addeddiisobutylaluminum hydride (1.5M in toluene, 8 mL) at −78° C. Afterstirring for 10 minutes the reaction mixture was quenched by addition ofwater. The precipitate was removed by filtration through diatomaceousearth. The filtrate was washed with water and brine and dried overNa₂SO₄. Filtration and evaporation of solvent provided the titlecompound.

Example 65C tert-butyl1-benzyl-2-(2-(2-phenyl-1,3-dioxolan-2-yl)ethyl)hydrazinecarboxylate

To a solution of tert-butyl 1-benzylhydrazinecarboxylate (2.3 g,prepared according to Eur. J. Org. Chem. 2010, 3815-3822) and EXAMPLE65B (2 g) in dichloromethane (30 mL) was added sodiumtriacetoxyborohydride (3.3 g). The mixture was stirred at roomtemperature, overnight. The mixture was diluted with ethyl acetate (300mL) and washed with aqueous NaOH, water, and brine and dried overNa₂SO₄. Filtration and evaporation of solvent gave the expected product.

Example 65D tert-butyl1-benzyl-2-(3-oxo-3-phenylpropyl)hydrazinecarboxylate

To a solution of EXAMPLE 65C (3.86 g) in acetone (5 mL) and water (5 mL)was added pyridinium p-toluenesulfonate (120 mg). The mixture wasstirred at 100° C. in a Biotage Initiator microwave reactor for 10minutes. The mixture was diluted with ethyl acetate (200 mL) and washedwith water and brine and dried over Na₂SO₄. Filtration and evaporationof the solvent gave the crude product which was used without furtherpurification in the next reaction.

Example 65E 1-benzyl-5-phenyl-1H-pyrazole

To a solution of EXAMPLE 65D (3.1 g) in dichloromethane (10 mL) wasadded TFA (10 mL) and the mixture was stirred overnight. The mixture wasconcentrated under vacuum and the residue was dissolved in ethyl acetate(300 mL) and washed with 2N aqueous NaOH, water and brine. The combinedorganic layers were concentrated, and the residue was dissolved indichloroethane (30 mL) and MnO₂ (2.5 g) was added. The mixture wasstirred overnight. Filtration and evaporation of the solvent providedthe title compound.

Example 65F 1-benzyl-4-iodo-5-phenyl-1H-pyrazole

To a solution of EXAMPLE 65E (270 mg) in N,N-dimethylformamide (5 mL)was added N-iodosuccinimide (259 mg). The mixture was stirred overnight.The mixture was diluted with ethyl acetate (200 mL) and washed withaqueous sodium bisulfite, water, and brine. The organic layers werecombined, and evaporation of the solvent provided the title compound.

Example 65G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

To a mixture of EXAMPLE 30A (200 mg) and EXAMPLE 65F (118 mg) in dioxane(9 mL) was added tetrakis(triphenylphosphine)palladium(0) (19 mg) andsaturated aqueous NaHCO₃ (3 mL). The mixture was purged with argon andstirred at 120° C. in a Biotage initiator microwave reactor for 30minutes. The mixture was diluted with ethyl acetate (200 mL) and washedwith water and brine and dried over Na₂SO₄. Filtration and evaporationof the solvent gave crude product which was loaded on a silica gelcartridge and eluted with 20% ethyl acetate in dichloromethane to givethe crude product which was dissolved in dichloromethane (3 mL) and TFA(3 mL) and stirred overnight. After evaporation of the solvent, theresidue was loaded on a silica gel cartridge and eluted with 5% methanolin dichloromethane to provide the title compound. ¹H NMR (300 MHz,CDCl₃) δ ppm 7.91 (dd, 3H), 7.75 (s, 1H), 7.64 (t, 1H), 7.54 (t, 1H),7.48 (m, 2H), 7.35 (d, 1H), 7.29 (m, 8H), 7.14 (m, 2H), 7.07 (m, 2H),6.81 (d, 1H), 5.36 (s, 2H), 5.20 (s, 1H), 3.78 (t, 2H), 3.11 (t, 2H)

Example 666-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 66A 1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-3-yl)methanol for (3-(dimethylamino)phenyl)methanoland 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 66B 5-methyl-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 66A for EXAMPLE63A in EXAMPLE 63B.

Example 66C4-iodo-5-methyl-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 66B for EXAMPLE65E in EXAMPLE 65F.

Example 66D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 30A (0.220 g), EXAMPLE 66C (0.100 g) andtetrakis(triphenylphosphine)palladium(0) (0.019 g) was added dioxane (3mL) and saturated aqueous NaHCO₃ solution (2 mL). The reaction wasdegassed with nitrogen then heated to 120° C. for 30 minutes. Themixture was partioned between ethyl acetate (75 mL) and water (75 mL)and filtered to remove solids. The organic layer was dried overmagnesium sulfate, filtered, and concentrated. Silica gelchromatography, eluting with a gradient of 0.5% to 3.0%methanol/dichloromethane, provided the title compound.

Example 66E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-3-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 66D for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52-7.40 (m, 3H),7.40-7.31 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.96 (d, 2H), 3.93 (ddd,3H), 3.75-3.64 (m, 1H), 3.59 (dd, 1H), 3.46-3.29 (m, 1H), 3.16 (s, 1H),3.01 (s, 2H), 2.11 (s, 3H), 2.02 (s, 1H), 1.81-1.52 (m, 2H), 1.45 (ddd,1H), 1.37-1.17 (m, 2H).

Example 676-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-phenylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 67A (1-phenylcyclohexyl)methanol

To a solution of 1-phenylcyclohexanecarboxylic acid (1.32 g) intetrahydrofuran (30 mL) at 0° C. was slowly added 2 M LiAlH₄ intetrahydrofuran (6.46 mL). The resulting mixture was stirred at roomtemperature overnight and cooled to 0° C. Ice water was added to quenchthe reaction. The resulting mixture was diluted with ethyl acetate andwashed with 1 N aqueous NaOH and water. The organic layer was dried overNa₂SO₄, filtered, and concentrated to provide the title compound.

Example 67B1-((1-phenylcyclohexyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 67A for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 67C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1-phenylcyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 67B for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 67D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-phenylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 67C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.04 (d, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.39-7.51 (m, 4H),7.32-7.39 (m, 2H), 7.25-7.32 (m, 2H), 7.14-7.24 (m, 3H), 6.87-6.94 (m,2H), 4.92 (s, 2H), 4.11 (s, 2H), 3.85 (t, 2H), 2.98 (t, 2H), 2.13 (s,2H), 1.51-1.65 (m, 4H), 1.42 (s, 1H), 1.16-1.33 (m, 3H).

Example 686-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 68A6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid tert butyl ester

64B (100 mg) was dissolved in dichloromethane (1 mL). Dimethylamine (2M,0.373 mL) was added, and the solution was stirred at room temperaturefor 15 minutes. Sodium triacetoxyborohydride (38 mg) was then added, andthe solution was stirred at room temperature for 16 hours. After thistime more dimethylamine (2M, 0.373 mL) and sodium triacetoxyborohydride(38 mg) was added, and the solution was stirred for another 16 hours.The crude material was then purified on silica gel using 20% methanol(dichloromethane).

Example 68B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{3-[(dimethylamino)methyl]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 68A for EXAMPLE7D in EXAMPLE 7E to isolate the title compound as the monotrifluoroacetic acid salt. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm12.84 (bs, 1H), 9.57 (bs, 1H), 8.04 (d, 1H), 7.92 (s, 1H), 7.80 (d, 1H),7.71 (d, 1H), 7.64-7.57 (m, 2H), 7.51-7.32 (m, 8H), 6.95 (d, 1H), 5.37(s, 2H), 4.95 (s, 2H), 4.25 (d, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.71(s, 3H), 2.70 (s, 3H).

Example 696-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 69A1-(3-methanesulfonyl-benzyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-3-(methylsulfonyl)benzene for EXAMPLE 4A in EXAMPLE 4B.

Example 69B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 69A for EXAMPLE58A in EXAMPLE 58B.

Example 69C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(methylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 69B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.99 (s, 1H), 7.89-7.84 (m, 3H), 7.78 (s, 1H),7.72 (d, 1H), 7.65-7.61 (m, 3H), 7.56-7.37 (m, 4H), 6.96 (d, 1H), 5.47(s, 2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.20 (s, 3H), 3.00 (t, 2H).

Example 706-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 70A 2-(5-cyclopropyl-1H-pyrazol-3-yl)isoindoline-1,3-dione

5-Cyclopropyl-1H-pyrazol-3-amine (5 g) was slurried in dioxane (80 mL)and N,N-dimethylformamide (80 mL), then phthalic anhydride (6 g) wasadded and the reaction was heated at 120° C. for 4 days. The reactionwas cooled and concentrated. The crude material was triturated withisopropyl ether/ethanol 1/1 (30 mL) to provide the title compound.

Example 70B2-(1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-3-yl)isoindoline-1,3-dione

EXAMPLE 70A (4.5 g) was dissolved in N,N-dimethylformamide (77 mL), then(bromomethyl)cyclohexane (4.0 g) was added, followed by 95% sodiumhydride (0.6 g). The reaction was heated at 70° C. for 2 hours. Thereaction mixture was then cooled, diluted with water and extracted withethyl acetate. The organic layer was washed with brine and the combinedaqueous layers were back-extracted with ethyl acetate. The combinedorganic layers were dried over Na₂SO₄. The crude material was purifiedby column chromatography on silica gel using 0-4% ethyl acetate indichloromethane to give a mixture of the title compound and the3-cyclopropyl isomer.

Example 70C 1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-3-amine

EXAMPLE 70B (1.4 g) was dissolved in ethanol (70 mL) then hydrazinehydrate (1.1 mL) was added and the reaction heated under reflux for 40minutes. The reaction was then cooled and filtered, and the filtrate wasconcentrated to give the crude product. The title compound was isolatedby column chromatography on silica gel using 0.5-2.0% methanol indichloromethane.

Example 70D 1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazole

EXAMPLE 70C (415 mg) was dissolved in tetrahydrofuran (12 mL), thenisoamyl nitrite (774 mg) was added and the reaction was heated at 60° C.overnight. The reaction was then cooled, concentrated, and purified bycolumn chromatography on silica gel using 85/15 hexanes/ethyl acetate.

Example 70E 4-bromo-1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 70D for EXAMPLE63B in EXAMPLE 63C.

Example 70F1-(cyclohexylmethyl)-5-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 70E for EXAMPLE84C in EXAMPLE 84D, except the crude product was purified by columnchromatography on silica gel using 5-12% ethyl acetate in hexanes.

Example 70G tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 70F for EXAMPLE22A in EXAMPLE 22B.

Example 70H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-cyclopropyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 70G for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.45 (m,2H), 7.36 (m, 2H), 7.22 (s, 1H), 6.93 (d, 1H), 4.96 (s, 2H), 3.97 (d,2H), 3.89 (t, 2H), 3.01 (t, 2H), 1.60-1.69 (m, 7H), 1.16 (m, 3H), 0.98(m, 2H), 0.79 (m, 2H), 0.25 (m, 2H).

Example 716-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 71A1-(3,5-di-tert-butylbenzyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting1-(bromomethyl)-3,5-di-tert-butylbenzene for EXAMPLE 4A in EXAMPLE 4B.

Example 71B tert-butyl6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 71A for EXAMPLE22A in EXAMPLE 22B.

Example 71C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3,5-di-tert-butylbenzyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 718 for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (brs, 1H), 8.04 (d, 1H), 7.93 (s, 1H), 7.79 (d, 1H), 7.69 (d, 1H), 7.61 (d,1H), 7.58 (s, 1H), 7.48 (m, 1H), 7.43 (d, 1H), 7.36 (t, 2H), 7.29 (m,1H), 7.05 (d, 2H), 6.94 (d, 1H), 5.29 (s, 2H), 4.95 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H), 1.24 (s, 18H).

Example 726-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 72A4-{2-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-ylmethyl]-benzenesulfonyl}-morpholine

The title compound was prepared by substituting1-(bromomethyl)-2-(phenylsulfonylmethyl)benzene for EXAMPLE 4A inEXAMPLE 4B.

Example 72B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 72A for EXAMPLE58A in EXAMPLE 58B.

Example 72C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-ylsulfonyl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 72B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(bs, 1H), 8.04 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.74 (d, 1H),7.65-7.52 (m, 5H), 7.51-7.32 (m, 5H), 6.97 (d, 1H), 5.74 (s, 2H), 4.96(s, 2H), 3.88 (t, 2H), 3.64 (m, 4H), 3.26 (m, 4H), 3.00 (t, 2H).

Example 736-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4,4-difluorocyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 73A (4,4-difluorocyclohexyl)methanol

To a solution of ethyl 4,4-difluorocyclohexanecarboxylate (1.000 g) indiethyl ether (5 mL) was added lithium aluminum hydride (1.0M intetrahydrofuran) (6.24 mL) at 0° C. The reaction was allowed to warm toroom temperature and was stirred for 2 hours. The reaction was cooled to0° C. and quenched with water (0.24 mL). 15% Aqueous NaOH (0.24 mL) wasadded followed by more water (0.72 mL). The reaction was stirred for 1hour, and magnesium sulfate was added. The mixture was filtered andconcentrated to provide the title compound.

Example 73B 1-((4,4-difluorocyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 73A for(3-(dimethylamino)phenyl)methanol and I H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 73C4-bromo-1-((4,4-difluorocyclohexyl)methyl)-5-methyl-1H-pyrazole

A solution of EXAMPLE 73B (0.795 g) in tetrahydrofuran (15 mL) wascooled to −40° C. n-BuLi (1.6 M in hexanes, 2.98 mL) was added and thereaction was stirred for 1 hour, then CH₃I (0.298 mL) was added and thereaction warmed to 0° C. The reaction was diluted with ethyl acetate (25mL) and washed with water (25 mL) and brine (25 mL). The combinedorganic layers were dried over magnesium sulfate, filtered andconcentrated. The residue was dissolved in N,N-dimethylformamide (10 mL)and N-bromosuccinimide (0.777 g) was added. After 1 hour, the reactionwas diluted with ethyl acetate (75 mL), washed with water (50 mL) andbrine (50 mL), dried over magnesium sulfate, filtered and concentrated.Silica gel chromatography eluting with a gradient of hexanes/ethylacetate provided the title compound.

Example 73D1-((4,4-difluorocyclohexyl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 73C for EXAMPLE84C in EXAMPLE 84D.

Example 73E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((4,4-difluorocyclohexyl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 73D for EXAMPLE22A in EXAMPLE 22B.

Example 73F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4,4-difluorocyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 73E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.56-7.40 (m, 3H), 7.36(ddd, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.09-3.81 (m, 4H),3.02 (d, 2H), 2.11 (s, 3H), 1.79 (m, 7H), 1.25 (d, 2H).

Example 746-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 74A (1-(trifluoromethyl)cyclohexyl)methanol

The title compound was prepared by substituting1-trifluoromethylcyclohexanecarboxylic acid for1-phenylcyclohexanecarboxylic acid in EXAMPLE 67A.

Example 74B4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1((1-(trifluoromethyl)cyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 74A for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 74C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(14(1-(trifluoromethyl)cyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 74B for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 74D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(trifluoromethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 74C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,2H), 8.04 (d, 1H), 7.80 (d, 1H), 7.69-7.73 (m, 2H), 7.57-7.63 (m, 2H),7.45-7.51 (m, 1H), 7.41-7.44 (m, 1H), 7.36 (t, 2H), 6.94 (d, 1H), 4.95(s, 2H), 4.42 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 1.46-1.73 (m, 9H),1.17-1.32 (m, 1H).

Example 756-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(diphenylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 75A 1-benzhydryl-4-bromo-1H-pyrazole

A solution of 4-bromo-1H-pyrazole (0.294 g), (bromomethylene)dibenzene(0.494 g) and triethylamine (0.418 mL) in tetrahydrofuran (5 mL) wasstirred at 60° C. for 24 hours. The reaction mixture was concentratedand purified by chromatography on silica gel using 0-20% ethylacetate/hexanes as eluent to provide the title compound.

Example 75B tert-butyl3-(1-benzhydryl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

A suspension of EXAMPLE 30A (100 mg), EXAMPLE 75A (77 mg),tris(dibenzylideneacetone)dipalladium(0) (7.47 mg),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (7.16 mg)and potassium phosphate (104 mg) in tetrahydrofuran (1.5 mL) and water(0.500 mL) was heated under microwave conditions (Biotage) at 80° C. for30 minutes. The reaction mixture was diluted with ethyl acetate, and theorganic layer was separated, dried and purified by chromatography onsilica gel using 10-60% ethyl acetate/hexanes as eluent to provide thetitle compound.

Example 75C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(diphenylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

A suspension of EXAMPLE 75B (30 mg) and lithium hydroxide (2 mg) intetrahydrofuran and methanol (2:1, 1 mL) was heated at 60° C. for 16hours. The reaction mixture was quenched with HCl (0.2 mL, 1M),concentrated and purified by chromatography on silica gel using 0-5%methanol/dichloromethane as eluent to provide the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 13.14 (s, 1H), 12.87 (s, 1H), 8.04(d, 1H), 7.82 (s, 1H), 7.79 (d, 1H), 7.73 (d, 1H), 7.66 (s, 1H), 7.61(d, 1H), 7.44-7.51 (m, 1H), 7.40-7.44 (m, 1H), 7.29-7.40 (m, 5H), 7.19(d, 4H), 6.93 (t, 2H), 4.94 (s, 2H), 3.94 (s, 1H), 3.86 (t, 2H), 2.99(t, 1H).

Example 766-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 76A 4-(2-((4-bromo-1H-pyrazol-1-yl)methyl)phenyl)morpholine

The title compound was prepared by substituting 4-bromo-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and(2-morpholinophenyl)methanol for (3-(dimethylamino)phenyl)methanol inEXAMPLE 34A.

Example 76B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-morpholinobenzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 76A for EXAMPLE77D in EXAMPLE 77E.

Example 76C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(morpholin-4-yl)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 76B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (d,1H), 7.57 (s, 1H), 7.40-7.51 (m, 2H), 7.36 (t, 2H), 7.24-7.32 (m, 1H),7.18-7.23 (m, 1H), 7.02-7.10 (m, 1H), 6.94 (d, 1H), 6.86-6.92 (m, 1H),5.41 (s, 2H), 4.94 (s, 2H), 3.87 (t, 2H), 3.72-3.78 (m, 4H), 3.00 (t,2H), 2.78-2.86 (m, 4H).

Example 776-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(morpholin-4-yl)-1-phenylpropyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 77A 1-(3,3-dimethoxy-1-phenylpropyl)-1H-pyrazole

To a solution of 1-benzyl-1H-pyrazole (0.653 g) in tetrahydrofuran (5mL) cooled to −78° C. was dropwise added 1.6M n-butyllithium (2.84 mL).The reaction mixture was stirred for 60 minutes, and2-chloro-1,1-dimethoxyethane (0.517 mL) was added, and stirringcontinued for 3 hours. The reaction mixture was allowed to slowly warmup to room temperature, and was quenched with water, extracted withether, dried over Na₂SO₄, filtered, and concentrated. The product waspurified by chromatography on silica gel using 0-20% ethylacetate/hexanes as the eluent to provide the title compound.

Example 77B 4-bromo-1-(3,3-dimethoxy-1-phenylpropyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 77A for EXAMPLE63B in EXAMPLE 63C.

Example 77C 3-(4-bromo-1H-pyrazol-1-yl)-3-phenylpropanal

A solution of EXAMPLE 77B (0.34 g) and hydrochloric acid (2 mL) intetrahydrofuran (3.5 mL) was stirred at room temperature for 16 hours.The reaction mixture was concentrated, redissolved in dichloromethane,dried over magnesium sulfate, filtered, and used in the next stepwithout purification.

Example 77D 4-(3-(4-bromo-1H-pyrazol-1-yl)-3-phenylpropyl)morpholine

A suspension of EXAMPLE 77C (150 mg), morpholine (0.117 mL), acetic acid(0.062 mL) and solid-supported MP-CNBH₃ (Argonaut Technologies, 885 mg,2.63 mmol/g) in dichloromethane (4 mL) and methanol (2 mL) was shaken atroom temperature for 18 hours. The reaction mixture was filtered,concentrated and purified by RP HPLC (30-100% CH₃CN/water/0.1% TFA) toprovide the title compound.

Example 77E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-morpholino-1-phenylpropyl)-1H-pyrazol-4-yl)picolinate

A suspension of EXAMPLE 30A (100 mg), EXAMPLE 77D (50 mg),tris(dibenzylideneacetone)dipalladium(0) (14 mg),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (24 mg)and potassium phosphate (104 mg) in tetrahydrofuran (3 mL) and water(1.5 mL) was heated under microwave conditions (Biotage) at 140° C. for5 minutes. The reaction mixture was diluted with ethyl acetate,separated, and purified by chromatography on silica gel using 10-60%ethyl acetate/hexanes as eluent to provide the title compound.

Example 77F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[3-(morpholin-4-yl)-1-phenylpropyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 77E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 9.65 (s, 1H), 8.04 (d, 1H), 7.97 (s, 1H), 7.79 (d, 1H), 7.72 (d,1H), 7.67 (s, 1H), 7.61 (d, 1H), 7.45-7.52 (m, 1H), 7.42 (t, 1H),7.29-7.39 (m, 7H) 6.95 (d, 1H), 5.57 (dd, 1H), 4.95 (s, 2H), 3.96 (d,4H), 3.82-3.90 (m, 2H), 3.60 (t, 2H), 3.46 (d, 2H), 3.04-3.17 (m, 4H),3.00 (t, 2H), 2.76-2.93 (m, 2H).

Example 786-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 78A tert-butyl4-((4-bromo-1H-pyrazol-1-yl)methyl)piperidine-1-carboxylate

The title compound was prepared by substituting 4-bromo-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole andtert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 78B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 78A for EXAMPLE77D in EXAMPLE 77E.

Example 78C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE75B in EXAMPLE 75C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.58-13.32 (m, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.76 (s, 1H), 7.69 (d,1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.45-7.51 (m, 1H), 7.39-7.44 (m, 1H),7.36 (t, 2H), 6.93 (d, 1H), 4.94 (s, 2H), 3.80-4.04 (m, 4H), 3.00 (t,2H), 2.69 (d, 2H), 1.86-2.02 (m, 1H), 1.45 (d, 2H), 1.37 (s, 9H),0.93-1.14 (m, 2H).

Example 796-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 79A 1-(2-(benzyloxy)benzyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting 3-methyl-4-iodopyrazolefor 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and1-(benzyloxy)-2-(bromomethyl)benzene for EXAMPLE 4A in EXAMPLE 4B.

Example 79B 2-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)phenol

In a 20 mL round-bottomed flask, EXAMPLE 79A (0.65 g) was added todichloromethane (5 mL) to give a solution. The solution was cooled to 0°C., and tribromoborane (1.7 mL, 1M in hexane) was added slowly. Afterstirring at room temperature for 4 hours, methanol (10 mL) was addedslowly. The solvent was removed, and the residue taken up intodichloromethane and purified by flash chromatography (Varian, SuperflashSF25-40 g column), eluting with 0-30% ethyl acetate/hexane to providethe title compound.

Example 79C

EXAMPLE 79B (0.05 g), 2-(morpholino)ethanol (0.03 g), di-tert-butylazodicarboxylate (0.06 g) and triphenylphosphine (0.1 g) were stirred atroom temperature overnight. The crude product was purified by flashchromatography (Varian, Superflash SF25-40 g column), eluting with 0-10%methanol in dichloromethane to provide the title compound.

Example 79D Tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-(2-(2-morpholinoethoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 79C for EXAMPLE77D in EXAMPLE 77E.

Example 79E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[2-(morpholin-4-yl)ethoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 79D for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 9.84 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.57 (m, 2H), 7.36 (m,6H), 7.08 (d, 1H), 6.94 (m, 2H), 6.66 (d, 1H), 5.32 (s, 2H), 4.96 (s,2H), 4.39 (m, 2H), 4.01 (m, 2H), 3.89 (t, 2H), 3.25 (m, 2H), 3.01 (t,2H), 2.07 (d, 3H).

Example 806-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 80A (2-(dimethylamino)phenyl)methanol

In a 250 mL round-bottomed flask, (3-(dimethylamino)phenyl)methanol (1g) and paraformaldehyde (2.5 g) were added to acetic acid (150 mL) togive a suspension. Sodium cyanoborohydride (2.6 g) was added slowly. Themixture was stirred at room temperature overnight. After concentrationof the solvent, water and ethyl acetate (1:1, 100 mL) were added. Afterseparation, the aqueous layer was extracted by ethyl acetate (2×20 mL).The combined organic layers were washed with water (3×50 mL), saturatedaqueous NaHCO₃ (2×30 mL), and dried over Na₂SO₄. After filtration andconcentration, the residue was taken up into CH₂Cl₂ and the product waspurified by flash chromatography (Varian, Superflash SF40-80 g column),eluting with 0-20% methanol/dichloromethane, to provide the titlecompound.

Example 80B 2-((4-iodo-1H-pyrazol-1-yl)methyl)-N,N-dimethylaniline

The title compound was prepared by substituting 4-iodopyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and EXAMPLE80A for EXAMPLE 4A in EXAMPLE 4B.

Example 80C Tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(dimethylamino)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 80B for EXAMPLE77D in EXAMPLE 77E.

Example 80D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(dimethylamino)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 80C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.89 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.61 (m,2H), 7.37 (m, 6H), 7.03 (m, 1H), 6.94 (d, 1H), 6.85 (d, 1H), 5.42 (s,2H), 4.95 (s, 2H), 3.87 (t, 2H), 3.00 (t, 2H), 2.71 (s, 6H).

Example 816-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[3-(morpholin-4-yl)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 81A4-(3-(2-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)phenoxy)propyl)morpholine

The title compound was prepared by substituting 3-morpholinopropan-1-olfor 2-morpholinoethanol in EXAMPLE 79C.

Example 81B Tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-(2-(3-morpholinopropoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 81A for EXAMPLE77D in EXAMPLE 77E.

Example 81C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{2-[3-(morpholin-4-yl)propoxy]benzyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 811B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.44 (m, 9H), 6.95 (m, 3H), 6.60 (d,1H), 5.29 (s, 2H), 4.96 (s, 2H), 4.12 (t, 2H), 3.95 (m, 4H), 3.57 (m,4H), 3.36 (m, 2H), 3.07 (m, 4H), 2.17 (m, 2H), 2.07 (s, 3H).

Example 826-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 82A (1-methylcyclohexyl)methanol

The title compound was prepared by substituting1-methylcyclohexanecarboxylic acid for ethyl4,4-difluorocyclohexanecarboxylate in EXAMPLE 73A.

Example 82B 1-((1-methylcyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 82A for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 82C 4-bromo-5-methyl-1-((1-methylcyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 82B for EXAMPLE63A in EXAMPLE 63B and then substituting that product for EXAMPLE 63B inEXAMPLE 63C.

Example 82D5-methyl-1-((1-methylcyclohexyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 82C for EXAMPLE63C in EXAMPLE 63D.

Example 82E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((1-methylcyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

A mixture of EXAMPLE 1D (0.240 g), EXAMPLE 82D (0.135 g),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.012 g),potassium phosphate (0.315 g) andtris(dibenzylideneacetone)dipalladium(0) (0.022 g) were added toN,N-dimethylformamide (0.6 mL), dioxane (0.4 mL) and water (0.2 mL). Thereaction was degassed with nitrogen, sealed and heated to 110° C. After3 hours the reaction was cooled, diluted with ethyl acetate (50 mL) andwashed with water (30 mL) and brine (30 mL). The reaction was dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatographyeluting with a gradient of 5% to 45% ethyl acetate/hexanes over 30minutes provided the title compound.

Example 82F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 82E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.85 (dt, 1H), 7.68-7.62(m, 1H), 7.59 (dd, 1H), 7.53 (d, 1H), 7.45-7.30 (m, 5H), 7.01 (d, 1H),5.17 (s, 2H), 3.89 (m, 4H), 3.12 (s, 2H), 2.09 (s, 3H), 1.49 (m, 10H),0.96 (s, 3H).

Example 836-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 83A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL)was added 5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoroacetic anhydride (40 mL) was added. The reaction mixturewas warmed to room temperature and stirred for 24 hours. The organiclayer was washed with brine, dried (Na₂SO₄), filtered, and concentratedto provide the title compound.

Example 83B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 83A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:1dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24 hours.The mixture was concentrated. Diethyl ether (4×200 mL) was added and themixture was filtered. The combined ether solution was concentrated toprovide the title compound.

Example 83C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 83B (53.8 g) and ether (400 mL),was added methanol (25 mL) slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted withether (3×100 mL). The combined extracts were dried (Na₂SO₄), filtered,and concentrated. The crude product was purified on silica gel with0-30% ethyl acetate/hexanes.

Example 83D1-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (340 mg) andEXAMPLE 83C (400 mg) were dissolved in toluene (12 mL).Cyanomethylenetributylphosphorane (462 mg) was added, and the solutionwas mixed at room temperature for 16 hours. The solution wasconcentrated and purified on silica gel using 10% ethyl acetate inhexanes.

Example 83E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 83D for EXAMPLE58A in EXAMPLE 58B.

Example 83F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 83E for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.05 (d, 1H), 7.80 (d, 1H), 7.71 (d, 1H), 7.61 (d, 1H),7.51-7.31 (m, 10H), 6.95 (d, 1H), 4.95 (s, 2H), 4.53 (s, 2H), 3.87 (t,2H), 3.00 (t, 2H), 2.05 (bs, 2H), 1.88 (t, 2H), 1.36 (t, 2H), 0.92 (s,6H).

Example 846-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 84A 1-(cyclohexylmethyl)-1H-pyrazole

The title compound was prepared by substituting (bromomethyl)cyclohexanefor (bromomethyl)cyclopentane in EXAMPLE 63A.

Example 84B 1-(cyclohexylmethyl)-5-ethyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 84A for EXAMPLE63A and ethyl iodide for iodomethane in EXAMPLE 63B.

Example 84C 4-bromo-1-(cyclohexylmethyl)-5-ethyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 84B for EXAMPLE63B in EXAMPLE 63C.

Example 84D1-(cyclohexylmethyl)-5-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

EXAMPLE 84C (225 mg) was placed into a flask and degassed with N₂.Tetrahydrofuran (3 mL) and toluene (2 mL) were added and the solutionwas cooled to −78° C. Triisopropyl borate (0.23 mL) was added, followedby dropwise addition of n-butyllithium (2.3 M in hexanes, 0.6 mL) over 5minutes. The mixture was stirred for 10 minutes at −78° C. and then adegassed solution of pinacol (135 mg) in tetrahydrofuran (1 mL) wasadded over 2 minutes. After stirring for 10 minutes at −78° C., thereaction was warmed to room temperature and stirred for 1 hour. Water(0.07 mL) was then added and the mixture was stirred for 2 hours. Thecrude reaction mixture was concentrated to dryness to provide the titlecompound.

Example 84E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 84D for EXAMPLE22A in EXAMPLE 22B.

Example 84F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(cyclohexylmethyl)-5-ethyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 84E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,1H), 12.61-12.90 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.79 (d, 1H),7.62 (d, 1H), 7.41-7.51 (m, 3H), 7.32-7.40 (m, 2H), 7.21 (s, 1H), 6.93(d, 1H), 4.95 (s, 2H), 3.88 (t, 2H), 3.83 (d, 2H), 3.01 (t, 2H), 2.54(q, 2H), 1.76-1.93 (m, 1H), 1.58-1.72 (m, 3H), 1.52 (d, 2H), 1.08-1.25(m, 3H), 0.96 (t, 3H), 0.89-1.05 (m, 2H).

Example 856-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 85A1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol for(3-(dimethylamino)phenyl)methanol and pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 85B1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 85A for EXAMPLE63A in EXAMPLE 63B.

Example 85C4-bromo-1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 85B for EXAMPLE63B in EXAMPLE 63C.

Example 85D1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 85C for EXAMPLE84C in EXAMPLE 84D.

Example 85E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(((1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 85D for EXAMPLE82D in EXAMPLE 82E.

Example 85F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 85E for EXAMPLE88 in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 12.77 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.47(m, 3H), 7.35 (m, 2H), 7.25 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.89(d, 2H), 3.84 (d, 2H), 3.01 (t, 2H), 2.49 (m, 1H), 2.08 (s, 3H), 2.04(m, 1H), 1.84 (m, 1H), 1.73 (m, 2H), 1.60 (t, 1H), 1.51 (m, 1H), 1.41(d, 1H), 1.35 (m, 1H), 1.15 (s, 3H), 0.78 (s, 3H).

Example 866-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 86A1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol for(3-(dimethylamino)phenyl)methanol and pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 86B1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86A for EXAMPLE63A in EXAMPLE 63B.

Example 86C4-bromo-1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86B for EXAMPLE63B in EXAMPLE 63C.

Example 86D 1-(((1S,2R,S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 86C for EXAMPLE84C in EXAMPLE 84D.

Example 86E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

A reaction vessel was charged with EXAMPLE 1D (200 mg), EXAMPLE 86D (183mg), tris(dibenzylideneacetone)dipalladium(0) (18.30 mg),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (10.34 mg)and K₃PO₄ (263 mg) and the vessel was sealed with a septum and purgedwith N₂. A sparged mixture of dioxane (1 mL) and water (1.000 mL) wasadded to the degassed reagents and the mixture was heated to 110° C. for5 hours. The reaction mixture was partitioned between water (15 mL) andethyl acetate (3×20 mL). The combined organics were washed with brine,dried (Na₂SO₄), filtered, and concentrated. The title compound waspurified by flash chromatography (gradient from 0 to 50% ethylacetate/hexanes).

Example 86F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 85E for EXAMPLE8B in EXAMPLE 8C. 1H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 12.56-13.01 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H),7.40-7.52 (m, 3H), 7.30-7.40 (m, 2H), 7.26 (s, 1H), 6.95 (d, 1H), 4.95(s, 2H), 3.91-4.09 (m, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.51-2.60 (m,1H), 2.21-2.36 (m, 1H), 2.11 (s, 3H), 1.68-1.98 (m, 5H), 1.54 (s, 1H),1.17 (s, 3H), 1.11 (s, 3H), 0.85 (d, 1H).

Example 876-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methylpropyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 87A (1-isobutylcyclohexyl)methanol

To a solution of lithium diisopropylamide (2.0 M, 7.74 mL) at −78° C.was added methyl cyclohexanecarboxylate (2.0 g) dropwise as a solutionin tetrahydrofuran (20 mL). After stirring for 30 minutes.1-iodo-2-methylpropane (1.956 mL) was added dropwise as a solution intetrahydrofuran (1 mL). The reaction was allowed to warm to roomtemperature and stirred overnight. The reaction was quenched with 1N HCl(25 mL) and diluted with water (25 mL) and extracted into diethyl ether(50 mL). The ether layer was washed with brine (30 mL), dried overmagnesium sulfate, filtered and concentrated. The residue was dissolvedin diethyl ether (25 mL) and lithium aluminum hydride (1.0M intetrahydrofuran, 16.88 mL) was added dropwise. After stirring overnight,the reaction was quenched with water (0.65 mL), 15% aqueous NaOH (0.65mL), more water (1.95 mL), then magnesium sulfate was added and thereaction filtered and concentrated. The residue was loaded onto silicagel and eluted using a gradient of 3% to 20% ethyl acetate/hexanes toprovide the title compound.

Example 87B1-((1-isobutylcyclohexyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 87A for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 87C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methylpropyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

EXAMPLE 1D (0.150 g), EXAMPLE 87B (0.119 g),bis(triphenylphosphine)palladium(II) dichloride (0.019 g) and cesiumcarbonate (0.259 g) were stirred together in N,N-dimethylformamide (0.45mL), dioxane (0.3 mL) and water (0.15 mL) in a microwave reactor at 120°C. for 15 minutes. The reaction was loaded onto silica gel and elutedusing a gradient of 5% to 50%. The corresponding ester was collected,treated with dichloromethane (0.5 mL) and TFA (0.5 mL) and stirredovernight. The reaction was concentrated, loaded onto silica gel andeluted using a gradient of 0.25% to 2.5% methanol/dichloromethane toprovide the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm13.19-12.64 (m, 2H), 8.08-8.00 (m, 1H), 7.82-7.76 (m, 1H), 7.74-7.67 (m,2H), 7.66-7.57 (m, 1H), 7.54 (s, 1H), 7.51-7.45 (m, 1H), 7.37 (d, 3H),6.94 (d, 1H), 4.94 (s, 2H), 4.03 (s, 2H), 3.87 (s, 2H), 3.00 (s, 2H),1.90-1.68 (m, 1H), 1.28 (m, 10H), 1.19-1.09 (m, 2H), 0.91 (d, 6H).

Example 886-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 88A methyl 1-(2-methoxyethyl)cyclohexanecarboxylate

To a cooled (−78° C.) solution of lithium diisopropylamide (2.0 M, 20mL) in tetrahydrofuran (20 mL) was added methyl cyclohexanecarboxylate(5.0 g) in tetrahydrofuran (30 mL). The mixture was stirred at −78° C.for 30 minutes and a solution of 1-bromo-2-methoxyethane (5.86 g) intetrahydrofuran (10 mL) was added. The mixture was stirred overnight andthe temperature was allowed to warm up to room temperature. The mixturewas quenched with aqueous NH₄Cl and extracted with ethyl acetate (200mL) and washed with water (3×), brine and dried over Na₂SO₄. Filtrationand evaporation of solvent gave crude product which was used in the nextreaction without further purification.

Example 88B (1-(2-methoxyethyl)cyclohexyl)methanol

A solution of EXAMPLE 88A (7.0 g) in diethyl ether (30 mL) was addeddropwise to a suspension of LiAlH₄ (1.32 g) in diethyl ether (50 mL).Once the addition was finished, the mixture was refluxed for 90 minutes.Then cooled to 0° C. and 2N NaOH (50 mL) was added slowly. Once asemi-solid appeared at the bottom of the flask, ethyl acetate (300 mL)was added and the mixture was stirred vigorously for 30 minutes. The topclear layer was decanted and more ethyl acetate (200) mL) was added tothe mixture and stirred for another 15 minutes. The top organic layerwas decanted and combined with the previous one. The combined organiclayers were washed with 2N aqueous NaOH, water, brine and dried overNa₂SO₄. Filtration and evaporation of solvent gave the title compound.

Example 88C1-((1-(2-methoxyethyl)cyclohexyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 88B for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 88D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

To a mixture of EXAMPLE 1D (162 mg) and EXAMPLE 88C (100 mg) in dioxane(9 mL) was added tetrakis(triphenylphosphine)palladium(0) (17 mg) andsaturated aqueous NaHCO₃ (3 mL). The mixture was purged with argon andstirred at 120° C. in a Biotage initiator microwave reactor for 30minutes. The mixture was diluted with ethyl acetate (200 mL) and washedwith water, brine and dried over Na₂SO₄. Filtration and evaporation ofsolvent gave crude product which was loaded on a silica gel cartridgeand eluted with 20% ethyl acetate in dichloromethane to give productwhich was dissolved in dichloromethane (3 mL) and TFA (3 mL) and stirredovernight. After evaporation of solvent, the residue was loaded on asilica gel cartridge and eluted with 5% methanol in dichloromethane togive the pure acid. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.72 (s, 2H), 7.68 (s, 1H), 7.61(d, 2H), 7.54 (m, 2H), 7.43 (m, 6H), 6.94 (d, 2H), 4.94 (s, 3H), 4.01(s, 2H), 3.87 (t, 2H), 3.39 (t, 2H), 3.21 (m, 2H), 3.00 (t, 2H), 1.38(m, 12H).

Example 896-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(2-methoxyethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 89A4-iodo-1-(2-(2-methoxyethoxy)benzyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting 2-methoxyethanol for2-morpholinoethanol in EXAMPLE 79C.

Example 89B Tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-(2-methoxyethoxy)benzyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 89A for EXAMPLE77D in EXAMPLE 77E.

Example 89C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(2-methoxyethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 89B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (m, 3H), 7.35 (m,3H), 7.24 (m, 1H), 7.03 (d, 1H), 6.96 (d, 1H), 6.87 (t, 1H), 6.69 (t,1H), 5.22 (s, 2H), 4.96 (s, 2H), 4.15 (m, 2H), 3.89 (t, 2H), 3.69 (m,2H), 3.32 (s, 3H), 3.02 (t, 2H), 2.10 (s, 3H).

Example 906-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 90A 1-((1-(2-methoxyethyl)cyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 88B for(3-(dimethylamino)phenyl)methanol and pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 90B1-((1-(2-methoxyethyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 90A for EXAMPLE63A in EXAMPLE 63B.

Example 90C4-iodo-1-((1-(2-methoxyethyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 90B for EXAMPLE65E in EXAMPLE 65F.

Example 90D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 90C forEXAMPLE 77D in EXAMPLE 77E, and then substituting the product from thatreaction for EXAMPLE 8B in EXAMPLE 8C. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.80 (d, 1H),7.40 (m, 8H), 7.29 (s, 1H), 6.96 (d, 2H), 4.95 (s, 2H), 3.88 (m, 4H),3.37 (t, 2H), 3.21 (s, 3H), 3.00 (t, 2H), 2.11 (s, 3H), 1.59 (t, 2H),1.34 (m, 10H).

Example 916-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 91A1-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-1H-pyrazole

The title compound was prepared by substituting(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethanol for(3-(dimethylamino)phenyl)methanol and pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 91B1-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 91A for EXAMPLE63A in EXAMPLE 63B.

Example 91C1-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-4-bromo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 91B for EXAMPLE63B in EXAMPLE 63C.

Example 91D1-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 91C for EXAMPLE84C in EXAMPLE 84D.

Example 91E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 91D for EXAMPLE86D in EXAMPLE 86E.

Example 91F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1R,2R,4R)-bicyclo[2.2.1]hept-5-en-2-ylmethyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 91E for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 12.56-13.05 (br s, 1H), 7.79 (d, 1H) 8.04 (d, 1H), 7.61 (d, 1H),7.50 (d, 1H), 7.40-7.50 (m, 2H), 7.32-7.40 (m, 2H), 7.27 (s, 1H), 6.95(d, 1H), 6.25 (dd, 1H), 6.08 (dd, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.76(dd, 1H), 3.64 (dd, 1H), 3.01 (t, 2H), 2.79 (m, 1H), 2.63 (m, 1H),2.54-2.59 (m, 1H), 2.11 (s, 3H), 1.75-1.85 (m, 1H), 1.33 (dd, 1H),1.20-1.26 (m, 1H), 0.59-0.67 (m, 1H).

Example 926-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,3-dimethylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 92A (3,3-dimethylcyclohexyl)methanol

To a suspension of (methoxymethyl)triphenylphosphonium chloride (3.26 g)in tetrahydrofuran (20 mL) at 0° C. was added n-butyllithium (2.5 M,5.94 mL) dropwise. The reaction was stirred for 15 minutes, then3,3-dimethylcyclohexanone (1.000 g) as a solution in tetrahydrofuran (3mL) was added dropwise. After the addition, the reaction was allowed towarm to room temperature and stir for 2 hours. The reaction was dilutedwith diethyl ether (50 mL) and washed with 1N aqueous HCl (50 mL), brine(50 mL), dried over magnesium sulfate, filtered and concentrated. Silicagel chromatography eluting with a gradient of 1% to 5% ethylacetate/hexanes gave the vinyl ether. The material was dissolved intetrahydrofuran (25 mL) and added HCl (27.7 mL) and stirred overnight.The reaction was diluted with diethyl ether (50 mL) and washed withbrine (50 mL), dried over magnesium sulfate and concentrated. Theresidue was dissolved in methanol (10 mL) and sodium borohydride (0.090g) was added and the mixture was stirred for 1 hours. The reaction wasdiluted with diethyl ether (50 mL) and washed with 1M aqueous HCl (50mL) and brine (50 mL). The combined organic layers dried over magnesiumsulfate, filtered, and concentrated. Silica gel chromatography elutingwith a gradient of 5% to 30% ethyl acetate/hexanes provided the titlecompound.

Example 92B1-((3,3-dimethylcyclohexyl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 92A for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 92C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,3-dimethylcyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 92B for EXAMPLE22A in EXAMPLE 22B.

Example 92D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,3-dimethylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 92C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.61 (d,1H), 7.52 (d, 1H), 7.51-7.45 (m, 1H), 7.44-7.32 (m, 3H), 6.94 (d, 1H),4.94 (s, 2H), 3.92-3.81 (m, 4H), 3.00 (t, 2H), 1.95 (s, 1H), 1.58-0.91(m, 6H), 0.85 (m, 6H), 0.79 (d, 2H).

Example 936-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 93A 1-(3-methoxy-1-phenylpropyl)-1H-pyrazole

The title compound was prepared by substituting 1-bromo-2-methoxyethanefor 2-chloro-1,1-dimethoxyethane in EXAMPLE 77A.

Example 93B 4-iodo-1-(3-methoxy-1-phenylpropyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 93A for EXAMPLE66B in EXAMPLE 66C.

Example 93C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 93B for EXAMPLE77D in EXAMPLE 77E.

Example 93D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(3-methoxy-1-phenylpropyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 93C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.98 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d,1H), 7.58 (s, 1H), 7.47 (t, 1H), 7.39-7.44 (m, 1H), 7.25-7.39 (m, 7H),6.94 (d, 1H), 5.51 (dd, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.09-3.24 (m,5H), 2.99 (t, 2H), 2.53-2.62 (m, 1H), 2.24-2.38 (m, 1H).

Example 946-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 94A 1-(4-methoxy-1-phenylbutyl)-1H-pyrazole

The title compound was prepared by substituting 1-bromo-3-methoxypropanefor 2-chloro-1,1-dimethoxyethane in EXAMPLE 77A.

Example 94B 4-iodo-1-(4-methoxy-1-phenylbutyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 94A for EXAMPLE65E in EXAMPLE 65F.

Example 94C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 94B for EXAMPLE77D in EXAMPLE 77E.

Example 94D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(4-methoxy-1-phenylbutyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 94C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.96 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d,1H), 7.57 (s, 1H), 7.44-7.52 (m, 1H), 7.40-7.44 (m, 1H), 7.21-7.39 (m,7H), 6.93 (d, 1H), 5.41 (dd, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 3.31 (t,2H), 3.18 (s, 3H), 2.24-2.40 (m, 1H), 2.03-2.19 (m, 1H), 1.27-1.47 (m,2H).

Example 956-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 95A methyl 2-phenyl-2-(1H-pyrazol-1-yl)acetate

The title compound was prepared by substituting dimethyl carbonate for2-chloro-1,1-dimethoxyethane in EXAMPLE 77A.

Example 95B methyl 3-bromo-2-phenyl-2-(1H-pyrazol-1-yl)acetate

The title compound was prepared by substituting EXAMPLE 95A for EXAMPLE63B in EXAMPLE 63C.

Example 95C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 95B for EXAMPLE77D in EXAMPLE 77E.

Example 95D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-methoxy-2-oxo-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 95C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.04 (d, 1H), 7.83 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.64 (s,1H), 7.61 (d, 1H), 7.31-7.51 (m, 9H), 6.93 (d, 1H), 6.52 (s, 1H), 4.94(s, 2H), 3.86 (t, 2H), 3.71 (s, 3H), 2.99 (t, 2H).

Example 966-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 96A 1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazole

The title compound was prepared by substituting cyclohexylmethylbromidefor 2-chloro-1,1-dimethoxyethane in EXAMPLE 77A.

Example 96B 1-(2-cyclohexyl-1-phenylethyl)-3-iodo-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 96A for EXAMPLE65E in EXAMPLE 65F.

Example 96C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 96B for EXAMPLE77D in EXAMPLE 77E.

Example 96D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(2-cyclohexyl-1-phenylethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 96C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.99 (s, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.61 (d,1H), 7.56 (s, 1H), 7.44-7.52 (m, 1H), 7.40-7.44 (m, 1H), 7.22-7.40 (m,7H), 6.94 (d, 1H), 5.51 (dd, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t,2H), 2.15-2.32 (m, 1H), 1.85-1.99 (m, 1H), 1.80 (d, 1H), 1.48-1.71 (m,4H), 0.86-1.14 (m, 6H).

Example 976-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 97A methyl 1-(3-methoxypropyl)cyclohexanecarboxylate

To a cooled (−78° C.) solution of lithium diisopropylamide (2.0 M, 12mL) in tetrahydrofuran (10 mL) was added methyl cyclohexanecarboxylate(1.42 g) in tetrahydrofuran (10 mL). The mixture was stirred at −78° C.for 30 minutes and a solution of 1-bromo-3-methoxypropane (1.73 g) intetrahydrofuran (10 mL) was added to the mixture. The mixture wasstirred overnight and the temperature was allowed to warm up to roomtemperature. The mixture was quenched with aqueous NH₄Cl and extractedwith ethyl acetate (200 mL) and washed with water (3×), brine and driedover Na₂SO₄. Filtration and evaporation of the solvent gave the crudeproduct which was used in the next reaction without furtherpurification.

Example 97B (1-(3-methoxypropyl)cyclohexyl)methanol

A solution of EXAMPLE 97A (2.14 g) in diethyl ether (10 mL) was addeddropwise to a suspension of LiAlH₄ (0.380 g) in diethyl ether (20 mL).Once the addition was finished, the mixture was refluxed for 90 minutes,and then cooled to 0° C. NaOH (2N, aqueous, 50 mL) was then addedslowly. The mixture was extracted with ethyl acetate (300 mL) and washedwith brine and dried over Na₂SO₄. Filtration and evaporation of thesolvent gave the title compound.

Example 97C 1-((1-(3-methoxypropyl)cyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 97B for(3-(dimethylamino)phenyl)methanol and pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 97D1-((1-(3-methoxypropyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 97C for EXAMPLE63A in EXAMPLE 63B.

Example 97E4-bromo-1-((1-(3-methoxypropyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 97D for EXAMPLE63B in EXAMPLE 63C.

Example 97F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 97E forEXAMPLE 86D in EXAMPLE 86E, and then substituting the product from thatreaction for EXAMPLE 8B in EXAMPLE 8C. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H),7.70 (m, 1H), 7.61 (d, 1H), 7.41 (m, 6H), 7.28 (s, 1H), 6.95 (d, 1H),4.95 (s, 3H), 3.88 (m, 4H), 3.27 (t, 2H), 3.02 (m, 2H), 2.10 (s, 3H),1.30 (m, 14H).

Example 986-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 98A4-Iodo-5-methyl-1-(2-((3-methyloxetan-3-yl)methoxy)benzyl)-1H-pyrazole

The title compound was prepared by substituting(3-methyloxetan-3-yl)methanol for 2-morpholinoethanol in EXAMPLE 79C.

Example 98B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{2-[3-hydroxy-2-(hydroxymethyl)-2-methylpropoxy]benzyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 98A forEXAMPLE 77D in EXAMPLE 77E, and then substituting the product from thatreaction for EXAMPLE 1E in EXAMPLE 1F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H),7.61 (d, 1H), 7.48 (m, 3H), 7.36 (m, 3H), 7.22 (t, 1H), 6.97 (t, 2H),6.82 (t, 1H), 6.47 (d, 1H), 5.26 (s, 2H), 4.96 (s, 2H), 3.41 (m, 4H),3.01 (t, 2H), 2.06 (s, 3H), 0.94 (s, 3H).

Example 996-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 99A4-iodo-5-methyl-1-(2-((tetrahydro-2H-pyran-4-yl)methoxy)benzyl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-4-yl)methanol for 2-morpholinoethanol in EXAMPLE79C.

Example 99B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-(2-((tetrahydro-2H-pyran-4-yl)methoxy)benzyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 99A for EXAMPLE77D in EXAMPLE 77E.

Example 99C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[2-(tetrahydro-2H-pyran-4-ylmethoxy)benzyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 99B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.03 (d, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.42 (m, 6H), 7.24 (t,1H), 6.98 (m, 2H), 6.85 (t, 1H), 6.61 (d, 1H), 5.23 (s, 2H), 4.95 (s,2H), 3.87 (m, 7H), 3.32 (t, 2H), 3.02 (t, 2H), 2.08 (s, 3H), 1.69 (m,2H), 1.36 (m, 2H).

Example 1006-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(1,4-dioxan-2-ylmethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 100A1-(2-((1,4-dioxan-2-yl)methoxy)benzyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting(1,4-dioxan-2-yl)methanol for 2-morpholinoethanol in EXAMPLE 79C.

Example 100B

Tert-butyl3-(1-(2-((1,4-dioxan-2-yl)methoxy)benzyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared by substituting EXAMPLE 100A for EXAMPLE77D in EXAMPLE 77E.

Example 100C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[2-(1,4-dioxan-2-ylmethoxy)benzyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 100B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 6H), 7.24 (t,1H), 6.99 (m, 2H), 6.87 (t, 1H), 6.65 (d, 1H), 5.23 (s, 2H), 4.96 (m,2H), 4.02 (m, 2H), 3.83 (m, 5H), 3.65 (m, 2H), 3.46 (m, 2H), 3.01 (t,2H), 2.10 (s, 3H).

Example 1016-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 101A 1-oxaspiro[2.5]octane

To a solution of trimethylsulfonium iodide (35.7 g) in dry DMSO (300 mL)was added cyclohexanone (9.82 g) with stirring. The mixture was broughtunder N₂ atmosphere and a solution of potassium tert-butoxide (16.83 g)in dry DMSO (200 mL) was slowly added. The resulting solution wasstirred at room temperature for 16 hours under N₂. The reaction mixturewas quenched by addition of water (600 mL), and extracted with diethylether (3×200 mL). The combined organic layers were washed with water(200 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide the title compound.

Example 101B 1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexanol

To a solution of 4-iodo-5-methyl-1H-pyrazole (2.08 g) inN,N-dimethylformamide (1 mL) was added EXAMPLE 101A (3.1 g) and Cs₂CO₃(5.34 g). The mixture was stirred at 120° C. for 5 minutes in a BiotageInitiator microwave reactor. The reaction mixture was diluted with ethylacetate (400 mL) and washed with water and brine and dried over Na₂SO₄.The mixture was filtered and concentrated under reduced pressure to givecrude product which was loaded on a 120 g silica gel column and elutedwith 10% ethyl acetate in hexane to provide the title compound.

Example 101C4-iodo-1-((1-(2-methoxyethoxy)cyclohexyl)methyl)-5-methyl-1H-pyrazole

To a solution of EXAMPLE 101B (260 mg) in tetrahydrofuran (15 mL) wasadded NaH (97 mg). The mixture was stirred for 30 minutes.1-Bromo-2-methoxyethane (564 mg) was added to the mixture and themixture was stirred for 3 hours. The mixture was then stirred at refluxfor 2 hours. Hexamethylphosphoramide (5 mL) and additional NaH (200 mg)were added to the mixture and the mixture was stirred at refluxovernight. The reaction mixture was diluted with ethyl acetate (200 mL)and washed with water and brine and dried over Na₂SO₄. The residue,after filtration and evaporation of the solvent, was loaded on a 40 gcolumn and eluted with 20% ethyl acetate in hexane to give the titlecompound.

Example 101D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 101C forEXAMPLE 77D in EXAMPLE 77E, and then substituting the product from thatreaction for EXAMPLE 1E in EXAMPLE 1F. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H),7.61 (d, 1H), 7.40 (m, 6H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 3H),4.05 (s, 2H), 3.89 (t, 2H), 3.46 (m, 4H), 3.25 (m, 3H), 3.01 (t, 2H),2.14 (m, 3H), 1.33 (m, 10H).

Example 1026-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylicacid Example 102A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-phenoxyphenyl)picolinate

The title compound was prepared by substituting 4-phenoxyphenylboronicacid for1-benzyl-4-(4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 102B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 102A for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.31-7.50(m, 8H), 7.15 (t, 1H), 6.97-7.05 (m, 5H), 4.98 (s, 2H), 3.91 (t, 2H),3.02 (t, 2H).

Example 1036-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylicacid Example 103A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-phenoxyphenyl)picolinate

The title compound was prepared by substituting 3-phenoxyphenylboronicacid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 103B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 103A for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62 (d, 1H), 7.33-7.50(m, 7H), 7.08-7.17 (m, 2H), 7.03 (d, 2H), 6.90-6.99 (m, 3H), 4.98 (s,2H), 3.90 (t, 2H), 3.01 (t, 2H).

Example 1046-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylicacid Example 104A Methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

The title compound was prepared by substituting methyl3-bromo-6-chloropicolinate for tert-butyl 3-bromo-6-chloropicolinate inEXAMPLE 1D.

Example 104B Methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4-nitrophenoxy)phenyl)picolinate

The title compound was prepared by substituting EXAMPLE 104A for EXAMPLE1D and 3-(4-nitrophenoxy)phenylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 104C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylicacid

To an ambient solution of EXAMPLE 104B (75 mg) in tetrahydrofuran (1.5mL) and water (0.5 mL) was added LiOH H₂O (13 mg). The reaction wasstirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, andacidified to pH ˜3 with 10% aqueous HCl solution. The layers wereseparated, and the aqueous layer was extracted with additional ethylacetate (2×8 mL). The combined organic layers were dried with anhydroussodium sulfate, filtered and concentrated under reduced pressure toprovide the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.85 (s, 1H), 8.26 (m, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H),7.62 (d, 1H), 7.43 (m, 5H), 7.26 (d, 1H), 7.14 (m, 4H), 7.00 (d, 1H),4.99 (s, 2H), 3.91 (t, 2H), 3.01 (t, 2H).

Example 1056-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylicacid Example 105A

2-(3-(4-chlorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (0.23 g),copper(II) acetate (0.19 g), triethylamine (0.218 g) and4-chlorophenylboronic acid (0.237 g) were stirred at room temperatureovernight. The solid was filtered off, and the solvent was removed underreduced pressure. The crude product was purified by flash chromatography(Varian, Superflash SF25-40 g column), eluting with 0-25% ethylacetate/hexane, to provide the title compound.

Example 105B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(4-chlorophenoxy)phenyl)picolinate

The title compound was prepared by substituting EXAMPLE 105A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 105C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 105B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64 (m, 2H), 7.41 (m, 7H), 7.05 (m,6H), 4.98 (s, 2H), 3.90 (t, 2H), 3.01 (t, 2H).

Example 1066-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylicacid Example 106A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-benzylphenyl)picolinate

The title compound was prepared by substituting 3-benzylphenylboronicacid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 106B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 106A for EXAMPLE88 in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.87 (s,2H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 2H), 7.41-7.50 (m, 2H),7.33-7.39 (m, 2H), 7.20-7.31 (m, 6H), 7.12-7.19 (m, 3H), 6.98 (d, 1H),4.98 (s, 2H), 3.86-3.96 (m, 4H), 3.01 (t, 2H).

Example 1076-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylicacid Example 107A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-chloro-2-methylphenyl)picolinate

The title compound was prepared by substituting3-chloro-2-methylphenylboronic acid for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 107B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(3-(cyclohexylmethyl)-2-methylphenyl)picolinate

A mixture of EXAMPLE 107A (60 mg),dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos, 4.58 mg)and tris(dibenzylideneacetone)dipalladium(0) (2.25 mg) intetrahydrofuran (0.5 mL) and 1-methyl-2-pyrrolidinone (0.5 mL) wasstirred at room temperature for 5 minutes while bubbling N₂ through thereaction mixture. To this solution was added 0.5 M(cyclohexylmethyl)zinc(II) bromide (0.393 mL) at room temperature. Thereaction mixture in a sealed tube was heated in a preheated oil bath at100(C overnight and cooled. The reaction mixture was quenched with waterand diluted with dichloromethane. The dichloromethane layer was washedwith water and concentrated. The residue was purified by flashchromatography, and eluted with 5% ethyl acetate in dichloromethane toprovide the title compound.

Example 107C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 107B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.49 (m, 3H),7.32-7.40 (m, 2H), 7.02-7.06 (m, 2H), 6.97 (d, 1H), 6.84 (dd, 1H), 4.98(d, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 1.97 (s, 3H), 1.40-1.70 (m, 7H),0.91-1.26 (m, 6H).

Example 1086-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid Example 108A 4-bromo-1-methyl-2-phenoxybenzene

A mixture of 5-bromo-2-methylphenol (1.0 g), phenylboronic acid (1.30g), Cu(OAc)₂ (0.97 g), and triethylamine (2.98 mL) in dichloromethane(50 mL) was stirred for 4 days. The mixture was diluted with ethylacetate, washed four times with 1M aqueous NaOH solution and once withbrine, dried over Na₂SO₄, filtered, and concentrated. The crude productwas chromatographed on silica gel using 2% ethyl acetate in hexanes toafford the title compound.

Example 108B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4-methyl-3-phenoxyphenyl)picolinate

A mixture of EXAMPLE 30A (172 mg), EXAMPLE 108A (74 mg), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg) indioxane (6 mL) and 2M aqueous Na₂CO₃ solution (3 mL) was stirred at 60°C. for 18 hours. The mixture was chromatographed on silica gel using2-20% ethyl acetate in hexanes to afford the title compound.

Example 108C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 108B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 2H), 7.49 (dd, 1H), 7.43(dd, 1H), 7.30-7.38 (m, 3H), 7.25 (dd, 1H), 7.16 (dd, 1H), 7.06 (m, 2H),6.95 (d, 1H), 6.91 (d, 1H), 6.87 (m, 2H), 4.96 (s, 2H), 3.88 (t, 2H),2.99 (t, 2H), 2.16 (s, 3H).

Example 1096-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylicacid Example 109A 2-bromo-1-methyl-4-phenoxybenzene

The title compound was prepared by substituting 3-bromo-4-methylphenolfor 5-bromo-2-methylphenol in EXAMPLE 108A.

Example 109B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-5-phenoxyphenyl)picolinate

The title compound was prepared by substituting EXAMPLE 109A for EXAMPLE108A in EXAMPLE 108B.

Example 109C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 109B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.55 (brs, 1H), 12.00 (br s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51(dd, 1H), 7.45 (dd, 2H), 7.35 (m, 4H), 7.23 (dd, 1H), 7.08 (t, 1H), 6.96(m, 3H), 6.87 (dd, 1H), 6.68 (d, 1H), 4.97 (s, 2H), 3.91 (t, 2H), 3.02(t, 2H), 2.04 (s, 3H).

Example 1106-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid Example 110A 1-bromo-2-methyl-3-phenoxybenzene

The title compound was prepared by substituting 3-bromo-2-methylphenolfor 5-bromo-2-methylphenol in EXAMPLE 108A.

Example 110B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-3-phenoxyphenyl)picolinate

The title compound was prepared by substituting EXAMPLE 1100A forEXAMPLE 108A in EXAMPLE 108B.

Example 110C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 110B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 1H), 12.00 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.54(d, 1H), 7.47 (dd, 2H), 7.34 (m, 4H), 7.24 (dd, 1H), 7.18 (dd, 1H), 7.06(t, 1H), 7.01 (dd, 2H), 6.90 (m, 3H), 4.99 (s, 2H), 3.93 (t, 2H), 3.03(t, 2H), 1.90 (s, 3H).

Example 1116-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylicacid Example 111A 1-bromo-2-methyl-4-phenoxybenzene

The title compound was prepared by substituting 4-bromo-3-methylphenolfor 5-bromo-2-methylphenol in EXAMPLE 108A.

Example 111B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-methyl-4-phenoxyphenyl)picolinate

The title compound was prepared by substituting EXAMPLE 111A for EXAMPLE108A in EXAMPLE 108B.

Example 111C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 111B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (brs, 1H), 12.00 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H),7.32-7.51 (m, 7H), 7.14 (t, 1H), 7.03 (m, 3H), 6.98 (d, 1H), 6.88 (d,1H), 6.78 (dd, 1H), 4.98 (s, 2H), 3.92 (t, 2H), 3.03 (t, 2H), 1.91 (s,3H).

Example 1126-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid Example 112A 1-Bromo-3-cyclohexylmethoxy-2-methyl-benzene

The title compound was prepared by substituting cyclohexylmethanol for(3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 112B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid tert-butyl ester

EXAMPLE 30A (125 mg), EXAMPLE 112A (87 mg),trans-dichlorobis(triphenylphosphine)palladium (II) (29 mg), and cesiumcarbonate (266 mg) were added to a microwave vial. N,N-dimethylformamide(0.9 mL), 1,4-dioxane (0.6 mL), and water (0.3 mL) were added. The vialwas placed in a microwave reactor and subjected to 120° C. for 15minutes. The solution was then added to water and extracted with 30%ethyl acetate in hexanes. The extract was washed with brine and driedover anhydrous sodium sulfate. The solution was filtered, concentratedand purified on silica gel using 30% ethyl acetate in hexanes.

Example 112C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 112B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H),7.08 (t, 1H), 6.98 (d, 1H), 6.86 (d, 1H), 6.62 (d, 1H), 4.98 (s, 2H),3.92 (t, 2H), 3.77 (d, 2H), 3.03 (t, 2H), 1.90 (s, 3H), 1.88-1.62 (m,6H), 1.31-1.03 (m, 5H).

Example 1136-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid Example 113A 1-bromo-4-cyclohexyloxy-2-methyl-benzene

The title compound was prepared by substituting cyclohexanol for(3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 113B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 113A for EXAMPLE112A in EXAMPLE 112B.

Example 113C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 113B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.34 (m, 5H),6.97-6.89 (m, 2H), 6.79 (dd, 1H), 6.71 (dd, 1H), 4.97 (s, 2H), 4.30 (m,1H), 3.91 (t, 2H), 3.02 (t, 2H), 2.02 (s, 3H), 1.97-1.85 (m, 2H),1.78-1.62 (m, 2H), 1.58-1.20 (m, 6H).

Example 1146-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid Example 114A 1-bromo-3-cyclohexyloxy-2-methyl-benzene

The title compound was prepared by substituting cyclohexanol for(3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 114B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 114A for EXAMPLE112A in EXAMPLE 112B.

Example 114C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 114B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.32 (m, 5H),7.07 (t, 1H), 6.97 (d, 1H), 6.91 (d, 1H), 6.61 (d, 1H), 4.98 (s, 2H),4.33 (m, 1H), 3.92 (t, 2H), 3.03 (t, 2H), 1.95-1.84 (m, 2H), 1.89 (s,3H), 1.77-1.63 (m, 2H), 1.57-1.26 (m, 6H).

Example 1156-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid Example 115A 1-Bromo-4-cyclohexylmethoxy-2-methyl-benzene

The title compound was prepared by substituting cyclohexylmethanol for(3-(dimethylamino)phenyl)methanol and 4-bromo-3-methylphenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 115B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 115A for EXAMPLE112A in EXAMPLE 112B.

Example 115C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 115B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.32 (m, 5H),6.96 (d, 1H), 6.91 (d, 1H), 6.79 (d, 1H), 6.70 (d, 1H), 4.97 (s, 2H),3.91 (t, 2H), 3.75 (d, 2H), 3.03 (t, 2H), 2.02 (s, 3H), 1.87-1.59 (m,6H), 1.31-1.00 (m, 5H).

Example 1166-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid Example 116A 2-bromo-6-(cyclohexyloxy)benzonitrile

To a solution of cyclohexanol (0.275 g) in N,N-dimethylformamide (5 mL)was added sodium hydride (60%, 0.069 g). After 30 minutes,2-bromo-6-fluorobenzonitrile (0.500 g) was added and the reactionstirred at room temperature for 2 hours. The reaction mixture wasdiluted with ethyl acetate (25 mL), washed with water (20 mL) and brine(20 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography eluting with a gradient of 3% to 10% ethylacetate/hexanes provided the title compound.

Example 116B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 116A forEXAMPLE 112A in EXAMPLE 112B, and then substituting the product fromthat reaction for EXAMPLE 8B in EXAMPLE 8C. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.79 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H),7.63 (d, 2H), 7.55 (dd, 1H), 7.51-7.31 (m, 4H), 7.21 (d, 1H), 7.04 (d,1H), 6.87 (d, 1H), 5.03 (s, 2H), 4.59 (s, 1H), 3.97 (d, 2H), 3.04 (s,2H), 1.91 (s, 2H), 1.71 (s, 2H), 1.62-1.26 (m, 6H).

Example 1176-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid Example 117A 1-bromo-2-chloro-3-(cyclohexyloxy)benzene

The title compound was prepared by substituting for cyclohexanol for(3-(dimethylamino)phenyl)methanol and 3-bromo-2-chlorophenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 117B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid

The title compound was prepared by first substituting EXAMPLE 117A forEXAMPLE 112A in EXAMPLE 112B, and then substituting the product fromthat reaction for EXAMPLE 8B in EXAMPLE 8C. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.79 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H),7.63 (d, 2H), 7.55 (dd, 1H), 7.51-7.31 (m, 4H), 7.21 (d, 1H), 7.04 (d,1H), 6.87 (d, 1H), 5.03 (s, 2H), 4.59 (s, 1H), 3.97 (d, 2H), 3.04 (s,2H), 1.91 (s, 2H), 1.71 (s, 2H), 1.62-1.26 (m, 6H).

Example 1186-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylicacid Example 118A (3-Bromo-2-methyl-phenyl)-cyclohexyl-amine

The title compound was prepared by substituting cyclohexanone forEXAMPLE 64B and 3-bromo-2-methylaniline for dimethylamine in EXAMPLE68A.

Example 118B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 118A for EXAMPLE112A in EXAMPLE 112B.

Example 118C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 118B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 6H),7.26-7.10 (m, 2H), 6.99 (d, 1H), 4.99 (s, 2H), 3.93 (t, 2H), 3.29 (bs,1H), 3.03 (t, 2H), 2.08-1.83 (m, 2H), 1.96 (bs, 3H), 1.80-1.70 (m, 2H),1.66-1.57 (m, 1H), 1.45-1.15 (m, 5H).

Example 1196-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylicacid Example 119A 1-Bromo-3-cyclohexyloxy-2-fluoro-benzene

The title compound was prepared by substituting cyclohexanol for(3-(dimethylamino)phenyl)methanol and 3-bromo-2-fluorophenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 119B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 119A for EXAMPLE112A in EXAMPLE 112B.

Example 119C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 119B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.65-7.58 (m, 2H), 7.51-7.32 (m,5H), 7.15-6.99 (m, 2H), 6.80 (td, 1H), 5.00 (s, 2H), 4.32 (m, 1H), 3.94(t, 2H), 3.02 (t, 2H), 1.98-1.87 (m, 2H), 1.77-1.66 (m, 2H), 1.58-1.22(m, 6H).

Example 1206-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylicacid Example 120A 1-Bromo-3-cyclohexyloxy-2-trifluoromethyl-benzene

Cyclohexanol (214 mg) was added to N,N-dimethylacetamide (10 mL), andsodium hydride (60% in mineral oil, 86 mg) was added. The solution wasmixed at room temperature for 15 minutes after which time1-bromo-3-fluoro-2-(trifluoromethyl)benzene (400 mg) was added. Thesolution was then heated at 100° C. for 1 hour. The solution was cooled,added to water, and extracted with diethyl ether. The extract was washedwith brine, dried over anhydrous sodium sulfate, and filtered. Thefiltrate was concentrated and purified on silica gel using 5% ethylacetate in hexanes.

Example 120B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 120A for EXAMPLE112A in EXAMPLE 112B.

Example 120C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 120B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.50-7.32 (m, 6H),7.22 (d, 1H), 6.99 (d, 1H), 6.64 (d, 1H), 4.99 (s, 2H), 4.57 (m, 1H),3.94 (t, 2H), 3.03 (t, 2H), 1.93-1.80 (m, 2H), 1.78-1.63 (m, 2H),1.60-1.18 (m, 6H).

Example 1216-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylicacid Example 121A1-bromo-3-(3,3-dimethyl-cyclohexyloxy)-2-methyl-benzene

The title compound was prepared by substituting 3,3-dimethylcyclohexanolfor (3-(dimethylamino)phenyl)methanol and 3-bromo-2-methylphenol for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 121B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 121A for EXAMPLE112A in EXAMPLE 112B.

Example 121C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 121B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.32 (m, 5H),7.08 (t, 1H), 6.97 (d, 1H), 6.91 (d, 1H), 6.61 (d, 1H), 4.98 (s, 2H),4.40 (m, 1H), 3.92 (t, 2H), 3.03 (t, 2H), 2.08-1.98 (m, 2H), 1.86 (s,3H), 1.81-1.72 (m, 2H), 1.69-1.45 (m, 2H), 1.37-1.20 (m, 2H), 0.96 (s,6H).

Example 1226-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylicacid Example 122A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-ethynylpicolinate

To a 50 mL pressure flask was added EXAMPLE 1D (1.0 g),ethynyltrimethylsilane (2.50 mL), and triethylamine (1.23 mL) intetrahydrofuran (18 mL). Bis(triphenylphosphine)palladium(II) dichloride(0.124 g) and CuI (0.034 g) were added, and the flask was flushed withnitrogen and sealed. The reaction was heated to 85° C. for 36 hours,cooled and passed through a plug of silica gel. After rinsing the silicagel with dichloromethane, the combined filtrates were concentrated byrotary evaporation, taken up in tetrahydrofuran (20 mL).tetra-n-Butylammonium fluoride (1M in tetrahydrofuran, 1.48 mL) wasadded dropwise at room temperature. The reaction was allowed to stir for2 hours. Saturated aqueous NH₄Cl solution was added and the aqueousportion was extracted three times with dichloromethane. The combinedorganics were dried over Na₂SO₄, filtered and concentrated. The residuewas purified by regular phase flash column chromatography (Analogix,0-100% ethyl acetate in hexanes) to provide the title compound.

Example 122B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-1,2,3-triazol-4-yl)picolinate

To a 4 mL vial was added EXAMPLE 122A (30 mg), benzyl bromide (10.05mg), and NaN₃ (4.58 mg) in N,N-dimethylformamide (0.5 mL) and water(0.12 mL). Sodium ascorbate (1.7 mg) and copper (II) sulfatepentahydrate (0.733 mg) was added and the mixture was heated at 70° C.overnight, cooled, and chromatographed by regular phase flash columnchromatography (Analogix, 0-100% ethyl acetate in hexanes) to providethe title compound.

Example 122C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylicacid

To a 10 mL round-bottomed flask was added EXAMPLE 122B (150 mg) indichloromethane (2.3 mL). TFA (1.2 mL) was added and the mixture wasstirred for 2 hours. The volatiles were removed under a stream of N₂.The residue was placed on high-vacuum for 1 hour and then purified byregular phase flash column chromatography (Analogix, 0-100% ethylacetate in hexanes) to provide the title compound. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 13.07 (s, 1H), 8.21 (s, 1H), 8.04 (d, 1H),7.98 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.51-7.27 (m, 9H), 6.98 (d,1H), 5.62 (s, 2H), 4.98 (s, 2H), 3.90 (t, 2H), 3.01 (t, 2H).

Example 1236-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylicacid Example 123A ethyl 1-benzyl-5-methyl-1H-pyrrole-2-carboxylate

Ethyl 5-methyl-1H-pyrrole-2-carboxylate (1.1 g) and benzyl bromide (1.35g) in N,N-dimethylformamide (30 mL) was treated with NaH (95%, 0.5 g)overnight. The reaction was quenched with ice water. The mixture wasdiluted with ethyl acetate and washed with brine. The organic layer wasdried over Na₂SO₄, filtered, and concentrated to provide the titlecompound.

Example 123B ethyl 1-benzyl-4-iodo-5-methyl-1H-pyrrole-2-carboxylate

To a solution of EXAMPLE 123A (564 mg) in acetone (8 mL) at 0° C. wasadded N-iodosuccinimide (600 mg). The mixture was stirred at roomtemperature overnight, and diluted with ethyl acetate and washed withwater. The organic layer was concentrated and the residue was purifiedby flash chromatography, and eluted with 50% dichloromethane in hexaneto provide the title compound.

Example 123C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 123B for EXAMPLE112A in EXAMPLE 112B.

Example 123D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-benzyl-5-(ethoxycarbonyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 123C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d, 1H), 7.42-7.50(m, 2H), 7.27-7.40 (m, 4H), 7.22 (t, 1H), 6.91-6.96 (m, 3H), 6.86 (s,1H), 5.63 (s, 2H), 4.96 (s, 2H), 4.12 (q, 2H), 3.89 (t, 2H), 3.01 (t,2H), 2.01 (s, 3H), 1.19 (t, 3H).

Example 1246-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-carboxy-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

EXAMPLE 123D (30 mg) in tetrahydrofuran (3 mL) and methanol (3 mL) wastreated with 2N aqueous NaOH (3 mL) overnight. The mixture was acidifiedto a pH of 5 with 1 M aqueous HCl and concentrated. The residue waspurified by RP-HPLC to provide the title compound. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ ppm 12.86 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H),7.61 (d, 1H), 7.41-7.53 (m, 3H), 7.27-7.39 (m, 4H), 7.22 (t, 1H),6.91-6.97 (m, 3H), 6.83 (s, 1H), 5.65 (s, 2H), 4.95 (s, 2H), 3.89 (t,2H), 3.01 (t, 2H), 1.99 (s, 3H).

Example 1256-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 125A1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole

The title compound was prepared by substituting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole for and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzylbromide for EXAMPLE 4A in EXAMPLE 4B.

Example 125B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 125A for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 125C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]3-(1-benzyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 125B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.60 (d, 1H), 7.45 (m,2H), 7.34 (m, 4H), 7.23 (m, 3H), 6.96 (t, 1H), 6.89 (d, 1H), 6.81 (m,1H), 6.19 (m, 1H), 5.08 (s, 2H), 4.91 (s, 2H), 3.84 (t, 2H), 2.99 (t,2H).

Example 1266-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid Example 126A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-tosyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrole for1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole inEXAMPLE 1E.

Example 126B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 126A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s,1H), 8.03 (d, 1H), 7.78 (m, 4H), 7.60 (d, 1H), 7.41 (m, 9H), 6.90 (d,1H), 6.49 (m, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t, 2H), 2.37 (s,3H).

Example 1276-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 127A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzoyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substitutingphenyl(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-1-yl)methanonefor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 1E.

Example 127B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 127A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.70 (m, 8H), 7.38 (m, 6H), 6.94 (d, 1H), 6.57 (m,1H), 4.95 (s, 2H), 3.87 (t, 2H), 3.01 (t, 2H).

Example 1286-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid Example 128A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(phenylsulfonyl)-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolefor 1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolein EXAMPLE 1E.

Example 128B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 128A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.83 (s,1H), 8.04 (d, 1H), 7.95 (m, 2H), 7.76 (m, 3H), 7.63 (m, 3H), 7.41 (m,6H), 6.91 (d, 1H), 6.51 (m, 1H), 4.94 (s, 2H), 3.86 (t, 2H), 2.99 (t,2H).

Example 1296-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 129A 1-benzyl-4-iodo-5-methyl-1H-pyrrole-2-carboxylic acid

EXAMPLE 123B (0.5 g) in tetrahydrofuran (20 mL) and methanol (10 mL) wastreated with 2 N NaOH (10 mL) overnight. The reaction mixture was cooledto 0° C., acidified to pH 5, diluted with water (30 mL) and concentratedto remove the organic solvent. The precipitates were collected byfiltration, washed with water and dried over sodium sulfate to providethe title compound.

Example 129B 1-benzyl-4-iodo-5-methyl-1H-pyrrole-2-carboxamide

To a solution of EXAMPLE 129A (450 mg) in tetrahydrofuran (12 mL) at 0°C. was added carbonyldiimidazole (642 mg). The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture was cooledto 0° C. and ammonium hydroxide (3 mL) was added. The mixture wasstirred at room temperature for 2 hours and concentrated. The residuewas dissolved in ethyl acetate, washed with brine and concentrated toprovide the title compound.

Example 129C 1-benzyl-4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

To a solution of EXAMPLE 129B (400 mg) in N,N-dimethylformamide (6 mL)and pyridine (0.6 mL) at (PC was added dropwise oxalyl chloride (0.31mL). The mixture was stirred at room temperature for 30 minutes, dilutedwith ethyl acetate and washed with saturated NaHCO₃ and waterextensively. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash chromatography, andeluted with dichloromethane to provide the title compound.

Example 129D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 129C for EXAMPLE112A in EXAMPLE 112B.

Example 129E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-5-cyano-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 129D for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.41-7.50(m, 2H), 7.28-7.40 (m, 5H), 7.04 (d, 2H), 6.96 (d, 1H), 6.90 (s, 1H),5.30 (s, 2H), 4.96 (s, 2H), 3.89 (t, 2H), 3.01 (t, 2H), 2.05 (s, 3H).

Example 1306-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylicacid Example 130A ethyl 4-iodo-5-methyl-1H-pyrrole-2-carboxylate

The title compound was prepared by following the procedure described forEXAMPLE 123B, replacing EXAMPLE 123A with ethyl5-methyl-1H-pyrrole-2-carboxylate.

Example 130B 4-iodo-5-methyl-1H-pyrrole-2-carboxylic acid

The title compound was prepared by following the procedure described forEXAMPLE 129A and replacing EXAMPLE 123B with EXAMPLE 130A.

Example 130C 4-iodo-5-methyl-1H-pyrrole-2-carboxamide

The title compound was prepared by following the procedure described forEXAMPLE 129B and replacing EXAMPLE 129A with EXAMPLE 130B.

Example 130D 4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared by following the procedure described forEXAMPLE 129C, replacing EXAMPLE 129B with EXAMPLE 130C.

Example 130E1-(cyclohexylmethyl)-4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

EXAMPLE 130D (100 mg), (bromomethyl)cyclohexane (382 mg) andtetrabutylammonium bromide (159 mg) in N,N-dimethylformamide was treatedwith sodium hydride (86 mg) and stirred at 50° C. overnight. Thereaction mixture was cooled, diluted with ethyl acetate and washed withbrine. The organic layer was concentrated. The residue was purified byflash chromatography (40% dichloromethane in hexanes) to provide thetitle compound.

Example 130F tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 130E for EXAMPLE112A in EXAMPLE 112B.

Example 130G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-cyano-1-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 130F for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41-7.52 (m, 3H),7.31-7.40 (m, 2H), 6.95 (d, 1H), 6.79 (s, 1H), 4.96 (s, 2H), 3.80-3.94(m, 4H), 3.01 (t, 2H), 2.09 (s, 3H), 1.45-1.77 (m, 6H), 1.10-1.24 (m,3H), 0.94-1.06 (m, 2H).

Example 1316-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-[1-(piperidin-1-yl)cyclohexyl]methyl)-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 131A (1-(piperidin-1-yl)cyclohexyl)methanol

The title compound was prepared by substituting1-phenylcyclohexanecarboxylic acid with1-(piperidin-1-yl)cyclohexanecarboxylic acid in EXAMPLE 67A.

Example 131B4-iodo-5-methyl-1-((1-(piperidin-1-yl)cyclohexyl)methyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 131A for(3-(dimethylamino)phenyl)methanol and EXAMPLE 130D for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 131C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-cyano-2-methyl-1-((1-(piperidin-1-yl)cyclohexyl)methyl)-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 131B for EXAMPLE112A in EXAMPLE 112B

Example 131D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(piperidin-1-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 131C for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.26 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52 (d,1H), 7.42-7.50 (m, 2H), 7.33-7.40 (m, 2H), 6.97 (d, 2H), 4.90-5.06 (m,2H), 4.46 (s, 2H), 3.90 (t, 2H), 3.25 (s, 2H), 3.02 (t, 2H), 1.92-2.20(m, 7H), 1.57-1.93 (m, 6H), 1.19-1.55 (m, 5H).

Example 1326,6′-bis[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3′-bipyridine-2,2′-dicarboxylicacid Example 132A di-tert-butyl6,6′-bis(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3,3′-bipyridine-2,2′-dicarboxylate

The title compound was isolated during the synthesis of EXAMPLE 79D as abyproduct.

Example 132B6,6′-bis[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3′-bipyridine-2,2′-dicarboxylicacid

The title compound was prepared by substituting EXAMPLE 132A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.83(br.s, 2H), 8.02 (d, 2H), 7.77 (d, 2H), 7.60 (d, 2H), 7.40 (m, 10H),6.97 (d, 2H), 4.97 (s, 4H), 3.92 (t, 4H), 3.01 (t, 4H).

Example 1336-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2-carboxylicacid Example 133A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1,2,3,4-tetrahydroisoquinolin-6-yl)picolinate

The title compound was prepared by substituting6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride for EXAMPLE 75A inEXAMPLE 75B.

Example 133B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)picolinate

A suspension of EXAMPLE 133A (20 mg), benzaldehyde (6.58 μL), MP-CNBH₃(100 mg, 2.47 mmol/g), acetic acid (2 μL) in dichloromethane (2mL)/methanol (2 mL) was shaken at room temperature for 18 hours. Thereaction mixture was filtered, washed with methanol/dichloromethane,concentrated and purified by RP HPLC (C8, 30-100% CH₃CN/water/0.1% TFA)to provide the title compound.

Example 133C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 133B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.96 (s,1H), 12.86 (s, 1H), 10.10 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.63 (d,2H), 7.60-7.41 (m, 7H), 7.36 (m, 2H), 7.26-7.15 (m, 3H), 6.99 (d, 1H),4.98 (s, 2H), 4.49 (d, 2H), 4.36 (s, 2H), 3.90 (t, 2H), 3.43-3.28 (m,2H), 3.10 (s, 2H), 3.02 (t, 2H).

Example 1346-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 134A methyl cycloheptanecarboxylate

To a solution of 25.0 g cycloheptanecarboxylic acid in methanol (300 mL)was added concentrated H₂SO₄ (0.5 g) and the mixture was stirred atreflux overnight. The reaction mixture was concentrated under vacuum andthe residue was diluted with ethyl ether (500 mL). The mixture waswashed with water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the title compound.

Example 134B methyl 1-(2-methoxyethyl)cycloheptanecarboxylate

To a cooled (−78° C.) solution of lithium diisopropylamide (2.0M, 6 mL)in tetrahydrofuran (10 mL) was added EXAMPLE 134A (1.60 g) intetrahydrofuran (10 mL). The mixture was stirred at −78° C. for 30minutes and a solution of 1-bromo-2-methoxyethane (1.73 g) intetrahydrofuran (10 mL) was added to the mixture. The mixture wasstirred overnight and allowed to warm up to room temperature. Themixture was quenched with aqueous NH₄Cl, extracted with ethyl acetate(200 mL), washed with water (3 times) and brine, and dried over Na₂SO₄.Filtration and concentration gave the crude product which was used inthe next reaction without further purification.

Example 134C (1-(2-methoxyethyl)cycloheptyl)methanol

A solution of EXAMPLE 134B (2.25 g) in diethyl ether (10 mL) was addeddropwise to a suspension of LiAlH₄ (0.40 g) in diethyl ether (20 mL).Once the addition was finished, the mixture was refluxed for 90 minutes,and cooled to 0° C. Aqueous NaOH (2N, 50 mL) was added slowly. Themixture was then extracted with ethyl acetate (300 mL) and the organiclayer was washed with brine and dried over Na₂SO₄. Filtration andconcentration provided the title compound.

Example 134D 1-((1-(2-methoxyethyl)cycloheptyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 134C for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 134E1-((1-(3-methoxypropyl)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 134D for EXAMPLE63A in EXAMPLE 63B.

Example 134F4-iodo-1-((1-(2-methoxyethyl)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 134E for EXAMPLE65E in EXAMPLE 65F.

Example 134G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 134F for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H),8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 6H), 6.95 (d, 1H),4.95 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.41 (t, 2H), 3.20 (s, 3H),3.01 (t, 2H), 2.11 (s, 3H), 1.43 (m, 16H)

Example 1356-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 78B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-dt) δ ppm 13.06 (s,1H), 12.86 (s, 1H), 8.45 (d, 1H), 8.15 (d, 1H), 8.04 (d, 1H), 7.80 (d,2H), 7.70 (d, 1H), 7.62 (d, 1H), 7.57 (d, 1H), 7.52-7.45 (m, 1H),7.45-7.30 (m, 3H), 6.95 (d, 1H), 4.95 (s, 2H), 4.05 (d, 2H), 3.87 (t,2H), 3.25 (d, 2H), 3.00 (t, 2H), 2.84 (dd, 2H), 2.10 (dd, 1H), 1.66 (d,2H), 1.33 (td, 2H).

Example 1366-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid Example 136A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)picolinate

The title compound was prepared by substituting picolinaldehyde forbenzaldehyde in EXAMPLE 133B.

Example 136B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 136A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 13.00 (s,1H), 12.86 (s, 1H), 10.56 (s, 1H), 8.71 (dd, 1H), 8.04 (d, 1H), 7.96(td, 1H), 7.79 (d, 1H), 7.68-7.56 (m, 3H), 7.55-7.42 (m, 3H), 7.36 (ddd,2H), 7.21 (d, 3H), 7.00 (d, 2H), 4.99 (s, 2H), 4.63 (s, 2H), 4.47 (s,2H), 3.93-3.88 (m, 2H), 3.63-3.55 (m, 2H), 3.13 (t, 2H), 3.02 (t, 2H).

Example 1376-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(cyclohexylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid Example 137A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]picolinate

The title compound was prepared by substituting cyclohexanecarbaldehydefor benzaldehyde in EXAMPLE 133B.

Example 137B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 137A for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.97 (s,1H), 12.87 (s, 1H), 9.42 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.67-7.59(m, 2H), 7.52-7.42 (m, 2H), 7.36 (ddd, 2H), 7.22 (s, 3H), 7.00 (d, 1H),4.99 (s, 2H), 4.58 (d, 1H), 4.30 (dd, 1H), 3.91 (t, 2H), 3.55 (d, 2H),3.40-3.25 (m, 2H), 3.18 (s, 1H), 3.12-2.98 (m, 4H), 1.96-1.55 (m, 6H),1.32-1.12 (m, 2H), 1.09-0.89 (m, 2H).

Example 1386-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylicacid Example 138A 2-(cyclohexyloxy)-4-iodo-3-methylpyridine

Cyclohexanol (0.501 g) in tetrahydrofuran (3.5 mL) was treated with NaH(0.1 g) until gas evolution ceased. 2-Fluoro-4-iodo-3-methylpyridine(0.237 g) in tetrahydrofuran (1.5 mL) was added. The reaction mixturewas stirred at room temperature for 0.5 hours and was quenched withice-water. The resulting mixture was extracted with ethyl acetate. Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered, and concentrated. The residue was purified by preparative TLC,and was eluted with petroleum ether to provide the title compound.

Example 138B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 138A for EXAMPLE1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.

Example 138C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 138B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 7.86-7.88(m, 1H), 7.73-7.74 (m, 1H), 7.23-7.48 (m, 7H), 6.95 (d, 1H), 6.50 (d,1H), 5.04-5.12 (m, 3H), 3.90-3.93 (m, 2H), 3.10-3.13 (m, 2H), 1.86-1.90(m, 2H), 1.85 (s, 3H), 1.66-1.68 (m, 2H), 1.17-1.50 (m, 6H).

Example 1396-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylicacid Example 139A 2-(cyclohexyloxy)-4-iodopyridine

The title compound was prepared by substituting 2-fluoro-4-iodo-pyridinefor 2-fluoro-4-iodo-3-methylpyridine in EXAMPLE 138A.

Example 139B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 139A for EXAMPLE1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.

Example 139C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 139B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.89 (s,1H), 8.11 (d, 1H), 8.04 (d, 1H), 7.76 (d, 1H), 7.73 (d, 1H), 7.63 (d,1H), 7.43-7.49 (m, 2H), 7.34-7.39 (m, 2H), 6.99 (d, 1H), 6.89 (d, 1H),6.67 (s, 1H), 5.01 (s, 3H), 3.92 (s, 2H), 3.02 (s, 2H), 1.95-1.98 (m,2H), 1.71-1.78 (m, 2H), 1.54-1.56 (m, 1H), 1.35-1.45 (m, 4H), 1.23-1.30(m, 1H).

Example 1406-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid Example 140A 4-iodo-2-phenoxypyridine

Phenol (0.464 g) in N,N-dimethylformamide (5 mL) was treated with sodiumhydride (60% in mineral oil, 0.057 g). After the gas evolution ceased,2-fluoro-4-iodopyridine (0.22 g) was added slowly to the solution. Themixture was heated at 100° C. overnight under nitrogen atmosphere,cooled, diluted with ethyl acetate and washed with aqueous NaOH. Theorganic layer was concentrated and purified by preparative TLC, elutingwith petroleum ether/ethyl acetate (10/1).

Example 140B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-phenoxy-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 140A for EXAMPLE1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.

Example 140C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 140B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.89 (s,1H), 8.03-8.12 (m, 2H), 7.78 (t, 2H), 7.63 (d, 1H), 7.34-7.49 (m, 6H),7.18-7.22 (m, 1H), 7.13 (d, 2H), 7.08 (d, 1H), 7.03 (d, 1H), 6.96 (s,1H), 4.95-5.06 (m, 2H), 3.93 (t, 2H), 3.01-3.04 (m, 2H).

Example 1416-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylicacid Example 141A 1-benzyl-3-bromo-1H-pyrrolo[2,3-b]pyridine

To a solution of 3-bromo-1H-pyrrolo[2,3-b]pyridine (500 mg) inN,N-dimethylformamide (10 mL) was added NaH (70 mg). The mixture wasstirred for 50 minutes, and (bromomethyl)benzene (0.290 mL) was addeddropwise. The reaction was stirred for 48 hours and quenched by theaddition of water and ethyl acetate. The layers were separated, and theorganic layer was washed with brine, dried with Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography,eluting with 2:1 hexane to ethyl acetate, to give the title compound.

Example 141B1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine

The title compound was prepared by substituting EXAMPLE 141A for EXAMPLE84C in EXAMPLE 84D.

Example 141C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 1418 for EXAMPLE22A in EXAMPLE 22B.

Example 141D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 141C for EXAMPLE88 in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (vbr s, 1H), 8.28 (s, 1H), 8.03 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.75(d, 1H), 7.63 (d, 1H), 7.62 (s, 1H), 7.46 (m, 2H), 7.40-7.20 (m, 7H)7.12 (m, 1H), 6.99 (d, 1H), 5.51 (s, 2H), 4.99 (s, 2H), 3.92 (br t, 2H),3.03 (br t, 2H).

Example 1426-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid Example 142A 4-iodo-3-methyl-2-phenoxypyridine

The title compound was prepared by substituting phenol for cyclohexanolin EXAMPLE 138A.

Example 142B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 142A for EXAMPLE1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.

Example 142C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 142B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 7.88 (d,1H), 7.72 (s, 1H), 7.47 (d, 1H), 7.38 (d, 1H), 7.28-7.32 (m, 4H),7.24-7.28 (m, 3H), 7.05-7.10 (m, 3H), 6.97 (d, 1H), 6.67 (d, 1H),5.09-5.13 (m, 2H), 3.84 (s, 2H), 3.04 (s, 2H), 2.01 (s, 3H).

Example 1436-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylicacid Example 143A 4-iodo-N,3-dimethyl-N-phenylpyridin-2-amine

2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylaniline (2.5 mL)was heated at 18° C. in a Biotage Initiator microwave reactor for 18hours. The reaction mixture was loaded onto a silica gel cartridge, andwas eluted with 0-100% dichloromethane in hexanes to provide the titlecompound.

Example 143B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3′-methyl-2′-(methyl(phenyl)amino)-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 143A for EXAMPLE1D and EXAMPLE 30A for EXAMPLE 82D in EXAMPLE 82E.

Example 143C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 143B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.24 (d, 1H), 7.76 (d,1H), 7.49 (d, 1H), 7.32-7.41 (m, 4H), 7.19-7.29 (m, 3H), 7.13-7.15 (m,2H), 6.96 (d, 1H), 6.71-6.77 (m, 4H), 5.07-5.13 (m, 2H), 3.80-3.83 (m,2H), 3.37 (s, 3H), 3.05 (t, 2H), 1.64 (s, 3H).

Example 1446-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(methoxymethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 144A methyl 1-(methoxymethyl)cyclohexanecarboxylate

The title compound was prepared by substituting bromomethylmethyl etherfor 1-bromo-2-methoxyethane and methyl cyclohexanecarboxylate forEXAMPLE 134A in EXAMPLE 134B.

Example 144B (1-(methoxymethyl)cyclohexyl)methanol

The title compound was prepared by substituting EXAMPLE 144A for EXAMPLE134B in EXAMPLE 134C.

Example 144C 1-((1-(methoxymethyl)cyclohexyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 144B for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 144D1-((1-(methoxymethyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 144C for EXAMPLE63A in EXAMPLE 63B.

Example 144E4-iodo-1-((1-(methoxymethyl)cyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 144D for EXAMPLE65E in EXAMPLE 65F.

Example 144F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(methoxymethyl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 144E for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),8.04 (d, 1H), 7.54 (m, 8H), 6.94 (d, 1H), 4.94 (s, 2H), 3.86 (t, 2H),3.28 (m, 4H), 3.03 (m, 4H), 1.23 (m, 10H).

Example 1456-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,3-dimethyl-1-(morpholin-4-yl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 145A 1-amino-3,3-dimethylcyclohexanecarbonitrile

To a solution of 3,3-dimethylcyclohexanone (1.89 g) in water (3.8 mL)and ethanol (4.5 mL) was added ammonium chloride (920 mg), followed byconcentrated ammonium hydroxide solution (2 mL) andtrimethylsilanecarbonitrile (1.71 g). The reaction was heated to 70° C.for 18 hours. The reaction was concentrated to dryness, and waspartitioned between water and methylene chloride. The layers wereseparated, and the aqueous layer was extracted with additional methylenechloride (3×25 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 40% ethyl acetate in petroleum ether, togive the title compound.

Example 145B 1-amino-3,3-dimethylcyclohexanecarboxamide

A solution of EXAMPLE 145A (4.6 g) in concentrated H₂SO₄ (9 mL) washeated to 70° C. for 20 minutes. The reaction mixture was cooled toabout 0° C. in an ice bath and diluted with water. The pH of thesolution was adjusted to pH 7-8 by addition of concentrated aqueousammonia solution. The aqueous layer was extracted with methylenechloride (2×50 mL). The combined organic layers were washed with water(1×20 mL), dried over MgSO₄, filtered, and concentrated to give thetitle compound, which was used in the next step without furtherpurification.

Example 145C ethyl 1-amino-3,3-dimethylcyclohexanecarboxylate

To a solution of EXAMPLE 145B (3.8 g) in water (25 mL) was addedconcentrated hydrochloric acid (25 mL). The reaction mixture was heatedto 110° C. for 3 hours, and then evaporated to dryness. The residue (3.5g) was dissolved in ethanol (30 mL), and sulfurous dichloride (10 g) wasadded. The resulting mixture was heated to 80° C. for about 18 hours,after which it was concentrated to dryness. The residue was diluted withsaturated aqueous NaHCO₃ solution and extracted with methylene chloride(2×25 mL). The organic layer was dried over MgSO₄, filtered andconcentrated. The residue was purified by silica gel chromatography,eluting with 2:1 petroleum ether/ethyl acetate, to give the titlecompound.

Example 145D ethyl 3,3-dimethyl-1-morpholinocyclohexanecarboxylate

To a solution of EXAMPLE 145C (3.5 g) in N,N-dimethylformamide (30 mL)was added 1-bromo-2-(2-bromoethoxy)ethane (5.8 g) and K₂CO₃ (6.5 g). Thereaction mixture was heated to 95° C. for 18 hours. The mixture wascooled to room temperature, diluted with water, and extracted withmethylene chloride (3×50 mL). The combined organic layers were washedwith saturated NaCl solution (1×25 mL), dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography,eluting with 4:1 petroleum ether/ethyl acetate solution, to give thetitle compound.

Example 145E (3,3-dimethyl-1-morpholinocyclohexyl)methanol

To a cooled (0° C.) solution of EXAMPLE 145D (3.7 g) in tetrahydrofuran(20 mL) was added lithium aluminum hydride (720 mg). The cooling bathwas removed, and the reaction mixture was stirred at room temperaturefor 3 hours. The reaction was quenched by the sequential addition ofwater (0.8 mL) and 15% aqueous NaOH solution (2 mL). The mixture wasdried with MgSO₄, filtered and concentrated to give the title compound,which was used in the subsequent step without further purification.

Example 145F4-((1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexyl)morpholine

The title compound was prepared by substituting EXAMPLE 145E for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 145G4-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexyl)morpholine

A solution of EXAMPLE 145F (0.53 g) in tetrahydrofuran (15 mL) wascooled to 0° C., and nBuLi (0.917 ml) was added dropwise. The reactionwas stirred at 0° C. for 30 minutes, and iodomethane (0.155 mL) wasadded. The cooling bath was removed, and the reaction mixture was warmedto room temperature. The reaction mixture was diluted with methylenechloride (50 mL) and washed with water (2×25 mL). The organic layer wasdried over magnesium sulfate, filtered, and concentrated. The residuewas dissolved in N,N-dimethylformamide (10 mL) and treated withN-bromosuccinimide (0.136 g). After 1 hour, the reaction mixture wasdiluted with methylene chloride (50 mL) and washed with water (2×25 mL).The organic layer was dried over magnesium sulfate, filtered, andconcentrated. The residue was purified by silica gel chromatography,eluting with a gradient of 0 to 75% ethyl acetate in hexanes, to givethe title compound.

Example 145H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[3,3-dimethyl-1-(morpholin-4-yl)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

A mixture of EXAMPLE 30A (0.192 g), EXAMPLE 145G (0.083 g),1,3,5,7-tetramethyl-6-tetradecane-2,4,8-trioxa-6-phosphaadamantane (9.25mg), potassium phosphate (0.167 g) and), andtris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.012 g) wasdissolved in tetrahydrofuran (2 mL) and water (0.66 mL). The reactionmixture was flushed with nitrogen and then heated under microwaveconditions (Biotage) to 140° C. for 5 minutes. The reaction was dilutedwith ethyl acetate (50 mL), washed with water (25 mL) and brine (25 mL),dried over magnesium sulfate, filtered, and concentrated. The residuewas purified by silica gel chromatography, eluting with a gradient of 5%to 100% ethyl acetate in hexane, to give the intermediate ester. Theresidue was dissolved in methylene chloride (0.5 mL) and treated withTFA (0.5 mL). The reaction mixture was stirred overnight andconcentrated to dryness. The residue was purified by RP-HPLC, elutingwith 10% to 70% acetonitrile in water containing 0.1% v/v TFA, to givethe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.85 (s,1H), 9.54 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.58-7.41(m, 4H), 7.41-7.30 (m, 2H), 6.98 (d, 1H), 4.97 (s, 3H), 4.57 (s, 6H),4.02 (s, 1H), 3.90 (t, 2H), 3.81-3.31 (m, 3H), 3.02 (t, 2H), 2.73 (s,1H), 2.20 (s, 2H), 2.01-1.39 (m, 4H), 1.33-0.70 (m, 6H).

Example 1466-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 146A 2-(3,3-dimethylcyclohexylidene)-1,3-dithiane

To a solution of (1,3-dithian-2-yl)trimethylsilane (5.0 g) intetrahydrofuran at −78° C. was added n-butyllithium (1.6M, 16.24 mL).After stirring for 30 minutes, 3,3-dimethylcyclohexanone (3.3 g) wasadded as a solution in tetrahydrofuran and the reaction mixture wasallowed to warm to room temperature. The reaction mixture was dilutedwith diethyl ether (100 mL), washed with water (50 mL) and brine (50mL), dried over magnesium sulfate, filtered, and concentrated. Silicagel chromatography eluting with a gradient of 0.13% to 2.5%ether/hexanes gave the title compound.

Example 146B methyl 3,3-dimethylcyclohexanecarboxylate

EXAMPLE 146A (2.00 g) and copper(II) sulfate pentahydrate (6.56 g) inmethanol (25 mL) were heated to 65° C. and stirred overnight. Thereaction mixture was filtered, rinsed with ether and concentrated. Theresidue was loaded onto silica gel and eluted using a gradient of 2% to20% ethyl acetate/hexanes to give the title compound.

Example 146C methyl1-(2-methoxyethyl)-3,3-dimethylcyclohexanecarboxylate

A solution of EXAMPLE 146B (0.60 g) in tetrahydrofuran (5 mL) was addedto lithium diisopropylamide (2.0 M, 2.10 mL) at −78° C. After stirringfor 30 minutes, 1-bromo-2-methoxyethane (0.64 g) was added and thereaction mixture was allowed to warm to room temperature. The reactionmixture was diluted with ether (75 mL), washed with water (50 mL) andbrine (50 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography eluting with 1-20% ethyl acetate in hexanesprovided the title compound.

Example 146D1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)-1H-pyrazole

To a solution of EXAMPLE 146C (0.37 g) in diethyl ether (5 mL) was addedLiAlH₄ (11.0M, 1.61 mL) dropwise. The reaction was stirred for 2 hoursat room temperature. The reaction mixture was cooled to 0° C., quenchedwith water (0.062 mL), 15% aqueous NaOH (0.062 mL), and then more water(0.17 mL) was added. The reaction mixture was stirred for 1 hour,magnesium sulfate was added, and the mixture was filtered andconcentrated. The residue was dissolved in toluene (5 mL), 1H-pyrazole(0.17 g) and cyanomethylenetributylphosphorane (0.47 g) were added andthe mixture was heated to 85° C. overnight. The reaction mixture wascooled, loaded onto silica gel and eluted with 1-10% ethyl acetate inhexanes to give the title compound.

Example 146E1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 146D for EXAMPLE63A in EXAMPLE 63B.

Example 146F4-iodo-1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 146E for EXAMPLE66B in EXAMPLE 66C.

Example 146G tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1-(2-methoxyethyl)-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 146F for EXAMPLE77D in EXAMPLE 77E.

Example 146H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethyl)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 146G for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.48 (dd, 2H), 7.46-7.41(m, 1H), 7.36 (ddd, 2H), 7.29 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H),3.96-3.73 (m, 4H), 3.20 (s, 3H), 3.00 (dd, 2H), 2.10 (s, 3H), 1.77-1.39(m, 4H), 1.36-0.99 (m, 8H), 0.93 (d, 6H).

Example 1476-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 147A methyl 1-(3-methoxypropyl)cycloheptanecarboxylate

The title compound was prepared by substituting 1-bromo-3-methoxypropanefor 1-bromo-2-methoxyethane in EXAMPLE 134B.

Example 147B (1-(3-methoxypropyl)cycloheptyl)methanol

The title compound was prepared by substituting EXAMPLE 147A for EXAMPLE134B in EXAMPLE 134C.

Example 147C 1-((1-(3-methoxypropyl)cycloheptyl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 147B for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 147D1-((1-(3-methoxypropyl)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 147C for EXAMPLE63A in EXAMPLE 63B.

Example 147E4-iodo-1-((1-(3-methoxypropyl)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 147D for EXAMPLE65E in EXAMPLE 65F.

Example 147F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(3-methoxypropyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 147E for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 5H), 7.27 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 3.80 (s, 3H), 3.27 (t, 2H), 3.21 (s, 3H),3.01 (t, 2H), 2.11 (s, 3H), 1.39 (m, 18H).

Example 148N-(1,3-benzothiazol-2-yl)-2-{5-(1-{[1-(2-methoxyethyl)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

To a solution of EXAMPLE 134G (50 mg) in dichloromethane (2 mL) wasadded methanesulfonamide (7.4 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (28 mg)and 4-dimethylaminopyridine (18 mg). The mixture was stirred overnight.The mixture was loaded on a silica gel column and eluted with 5%methanol in dichloromethane to give the pure product. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 8.03 (d, 1H), 7.79 (d, 1H), 7.60 (s, 1H),7.41 (m, 5H), 7.30 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 3.94 (m, 2H),3.83 (s, 2H), 3.42 (t, 2H), 3.41 (s, 3H), 3.27 (s, 3H), 3.21 (m, 3H),3.11 (m, 2H), 2.12 (s, 3H), 1.45 (m, 16H)

Example 1496-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 149A1-((tetrahydro-2H-pyran-2-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-2-yl)methanol for (3-(dimethylamino)phenyl)methanolin EXAMPLE 34A.

Example 149B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 149A for EXAMPLE82D in EXAMPLE 82E.

Example 149C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 149B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.96-13.25 (m, 1H), 12.85 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.76 (s,1H), 7.71 (d, 1H), 7.61 (d, 1H), 7.53 (s, 1H), 7.32-7.51 (m, 4H), 6.94(d, 1H), 4.94 (s, 2H), 4.08 (d, 2H), 3.80-3.90 (m, 3H), 3.58-3.67 (m,1H), 3.24-3.34 (m, 1H), 3.00 (t, 2H), 1.73-1.80 (m, 1H), 1.49-1.57 (m,1H), 1.36-1.49 (m, 3H), 1.09-1.24 (m, 1H).

Example 1506-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 150A(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptane-3-carbaldehyde

To a solution of(1S,5R)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene (940 mg)in tetrahydrofuran (5 mL) was added dropwise 9-borabicyclo[3.3.1]nonane(0.5 M in tetrahydrofuran, 10.43 mL). The reaction mixture was heated toreflux overnight, then cooled to −35° C. and then placed under a COatmosphere (1 atm). LiAl(OtBu)₃H (1M in tetrahydrofuran, 5.21 mL) wasadded dropwise over 30 minutes. Following the addition, the reactionmixture was stirred for 1.5 hours under CO (1 atm), during which timethe reaction temperature was increased to 0° C. The mixture was warmedto room temperature and stirred for 45 minutes, then the system wasflushed with argon and a buffer solution (5.28 g NaH₂PO₄ and 6.86 gK₂HPO₄ in 20 mL water) was added. The flask was chilled in a −10° C.cooling bath and the reaction was quenched by dropwise addition of 30%aqueous H₂O; solution (2.2 mL), then warmed to room temperature andstirred for 15 minutes. The reaction mixture was partitioned betweenwater (50 mL) and ethyl acetate (3×75 mL). The organic phase was thenwashed with 10% Na₂S₂O₃ (3×50 mL) and brine (50 mL), then dried (MgSO₄),filtered, and concentrated. The crude product was purified by flashchromatography on silica gel eluting with 0 to 50% ethyl acetate inhexanes to give the title compound.

Example 150B((1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methanol

To a solution of EXAMPLE 150A (407 mg) in tetrahydrofuran (10 mL), whichwas cooled in a room temperature water bath, was added dropwise LAH(1.0M in tetrahydrofuran, 2.3 mL). The reaction was stirred at roomtemperature for 1 hour then quenched with water (25 mL). The resultingsuspension was filtered through diatomaceous earth, and the filter cakewas rinsed with ether (50 mL). The layers were separated and the aqueouslayer was extracted with ether (2×25 mL). The extracts were washed withbrine (25 mL), dried (MgSO₄), filtered, and concentrated to give thetitle compound, which was used without further purification.

Example 150C1-(((1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 150B for(3-(dimethylamino)phenyl)methanol in EXAMPLE 34A.

Example 150D tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(((1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-3-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 150C for EXAMPLE82D in EXAMPLE 82E.

Example 150E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1R,2R,3R,5S)-2-(2-methoxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 150D for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, DMSO-d) δ ppm 12.89-13.24 (m, 1H),12.85 (s, 1H), 8.04 (d, 1H), 7.87 (s, 1H), 7.79 (d, 1H), 7.70 (d, 1H),7.61 (d, 1H), 7.54 (s, 1H), 7.45-7.51 (m, 1H), 7.40-7.45 (m, 1H),7.32-7.39 (m, 2H), 6.95 (d, 1H), 4.94 (s, 2H), 3.90-4.10 (m, 2H), 3.87(t, 2H), 3.20-3.31 (m, 2H), 3.15 (s, 3H), 3.00 (t, 2H), 2.19-2.31 (m,2H), 1.81-1.93 (m, 3H), 1.71-1.80 (m, 1H), 1.47-1.63 (m, 2H), 1.31-1.44(m, 1H), 1.16 (s, 3H), 0.94 (s, 3H), 0.75 (d, 1H).

Example 1516-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 151A 1-oxaspiro[2.6]nonane

To a mixture of trimethylsulfonium iodide (35.7 g) in 300 mL dry DMSOwas added 11.2 g of cycloheptanone with stirring. A solution ofpotassium tert-butoxide (16.83 g) in 200 mL dry DMSO was slowly added.The resulting solution was stirred at room temperature for 16 hours. Thereaction mixture was quenched by addition of water (600 mL), andextracted with diethyl ether (3×200 mL). The combined organic layerswere washed with water (200 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give the product.

Example 151B 1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cycloheptanol

The title compound was prepared by substituting EXAMPLE 151A for EXAMPLE141A in EXAMPLE 141B.

Example 151C4-iodo-1-((1-(2-methoxyethoxy)cycloheptyl)methyl)-5-methyl-1H-pyrazole

To a solution of EXAMPLE 151B (356 mg) in N,N-dimethylacetamide (6 mL)was added NaH (128 mg, 60% in mineral oil). The mixture was stirred for30 minutes. Then, 1-bromo-2-methoxyethane (740 mg) was added to themixture, which was stirred overnight. The reaction mixture was dilutedwith ethyl acetate (200 mL) and washed with water, brine and dried overNa₂SO₄. After filtration and concentration, the residue containing thecrude title compound was used in the next reaction without furtherpurification.

Example 151D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 151C for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 4.03 (s, 2H), 3.89 (t, 2H), 3.39 (t, 2H),3.21 (m, 3H), 3.01 (t, 2H), 2.13 (s, 3H), 1.43 (m, 14H).

Example 1526-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[1-cyclohexyl-3-(morpholin-4-yl)propyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 152A 3-cyclohexyl-3-(1H-pyrazol-1-yl)propanal

A solution of (E)-3-cyclohexylacrylaldehyde (4.94 g) (made according toOrganic Letters (2011), 13(1), 70-73),2-(bis(3,5-bis(trifluoromethyl)phenyl)-(trimethylsilyloxy)methyl)pyrrolidine(0.712 g) and 4-nitrobenzoic acid (0.124 mL) in toluene (60 mL) wasstirred at room temperature for 10 minutes and 1H-pyrazole (1.622 g) wasadded. The reaction mixture was stirred for 3 days, and purified byflash chromotography (silica gel, 0-50% ethyl acetate/hexanes).

Example 152B 4-(3-cyclohexyl-3-(1H-pyrazol-1-yl)propyl)morpholine

The title compound was prepared by substituting EXAMPLE 152A forbenzaldehyde and morpholine for EXAMPLE 133A in EXAMPLE 133B.

Example 152C4-(3-cyclohexyl-3-(5-methyl-1H-pyrazol-1-yl)propyl)morpholine

The title compound was prepared by substituting EXAMPLE 152B for EXAMPLE63A in EXAMPLE 63B.

Example 152D4-(3-(4-bromo-5-methyl-1H-pyrazol-1-yl)-3-cyclohexylpropyl)morpholine

The title compound was prepared by substituting EXAMPLE 152C for EXAMPLE63B in EXAMPLE 63C.

Example 152E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(1-cyclohexyl-3-morpholinopropyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 152D for EXAMPLE77D in EXAMPLE 77E.

Example 152F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[1-cyclohexyl-3-(morpholin-4-yl)propyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 152E for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,1H), 9.63 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53-7.42(m, 3H), 7.36 (dd, 3H), 6.97 (d, 1H), 6.51 (s, 1H), 4.97 (s, 2H),4.00-3.85 (m, 5H), 3.58 (t, 2H), 3.02 (t, 2H), 2.31-2.18 (m, 2H),1.93-1.69 (m, 4H), 1.60 (d, 2H), 1.28-0.79 (m, 8H).

Example 1536-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]3-(1-benzyl-1H-indazol-5-yl)pyridine-2-carboxylicacid Example 153A1-benzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The title compound was prepared by substituting5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzylbromide for EXAMPLE 4A in EXAMPLE 4B.

Example 153B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-indazol-5-yl)picolinate

The title compound was prepared by substituting EXAMPLE 153A for EXAMPLE22A in EXAMPLE 22B.

Example 153C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-5-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 153B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (vbr s, 1H), 8.12 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.69 (m, 3H), 7.62(d, 1H), 7.46 (m, 2H), 7.39-7.20 (m, 8H), 6.99 (d, 1H), 5.66 (s, 2H),4.99 (s, 2H), 3.91 (br t, 2H), 3.02 (br t, 2H).

Example 1546-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 154A4-bromo-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting(tetrahydro-2H-pyran-2-yl)methanol for (3-(dimethylamino)phenyl)methanoland 4-bromo-1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 154B 4-bromo-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole

A solution of EXAMPLE 154A (0.25 g) in tetrahydrofuran (2 mL) was cooledto −78° C. and treated with lithium diisopropylamide (prepared fromdiisopropylamine (0.12 g) and n-butyllithium (0.77 mL, 1.6 M). Afterstirring for 1 hour, methyl iodide (0.19 mL) was added and the reactionmixture was allowed to warm to room temperature. The reaction wasdiluted with ether (100 mL) and washed with water (3×75 mL) and brine(75 mL), dried over magnesium sulfate, filtered, and concentrated.Silica gel chromatography eluting with a gradient of 5% to 30% ethylacetate/hexanes provided the title compound.

Example 154C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((tetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 154B for EXAMPLE77D in EXAMPLE 77E.

Example 154D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 154C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52-7.41 (m, 3H), 7.36(m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.15-3.76 (m, 5H),3.73-3.55 (m, 1H), 3.27 (m, 1H), 3.01 (t, 2H), 2.12 (s, 3H), 1.77 (m,1H), 1.60-1.33 (m, 4H), 1.24 (m, 1H).

Example 1556-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-{(1-[3-(morpholin-4-yl)propoxy]cycloheptyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 155A1-((1-(allyloxy)cycloheptyl)methyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting 3-bromoprop-1-ene for1-bromo-2-methoxyethane in EXAMPLE 151C.

Example 155B3-(1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cycloheptyloxy)propan-1-ol

To a solution of EXAMPLE 155A (1.7 g) in tetrahydrofuran (20 mL) wasadded a 0.5 M 9-borabicyclo[3.3.1]nonane-tetrahydrofuran solution (50mL, 0.5 M) at 0° C. After the reaction mixture was stirred for 24 hoursat room temperature, a 0.5 M NaOH aqueous solution (30 mL) and 30% H₂O₂aqueous solution (5.5 mL) were added. After the reaction mixture wasstirred for 16 hours, the reaction was then quenched by adding water (15mL). The reaction mixture was extracted with ethyl acetate, and theorganic layer was washed with water and a saturated aqueous NaClsolution. After the organic layer was dried over Na₂SO₄, and filtered,the solvent was evaporated under reduced pressure. The crude product waspurified on a silica gel column, eluting with 10-50% ethyl acetate inhexanes, to provide the title compound.

Example 155C3-(1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cycloheptyloxy)propanal

To a solution of EXAMPLE 155B (393 mg) in dichloromethane (20 mL) wasadded Dess-Martin Periodinane (425 mg). After the reaction mixture wasstirred for 4 hours at room temperature, 2N NaOH aqueous solution (10mL) was added and the reaction mixture was extracted with ethyl acetate.The organic layer was washed with water and a saturated NaCl solution.After the organic layer was dried over Na₂SO₄ and filtered, the solventwas removed under reduced pressure. The crude product was used in thenext step without further purification.

Example 155D4-(3-(1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cycloheptyloxy)propyl)morpholine

To a solution of EXAMPLE 155C (393 mg) in dichloromethane (20 mL) wasadded morpholine (263 mg) and sodium triacetoxyborohydride (427 mg).After the reaction mixture was stirred overnight at room temperature, 2NNaOH aqueous solution (10 mL) was added and the reaction mixture wasextracted with ethyl acetate, and the organic layer was washed withwater and a saturated NaCl solution. After the organic layer was driedover Na₂SO₄, it was filtered and the solvent was evaporated underreduced pressure. The crude product was used in the next reactionwithout further purification.

Example 155E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[3-(morpholin-4-yl)propoxy]cycloheptyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 155D for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),9.28 (m, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 (m, 5H),6.96 (d, 1H), 4.97 (m, 2H), 3.99 (m, 5H), 3.09 (m, 6H), 2.15 (m, 3H),1.91 (s, 2H), 1.53 (m, 14H).

Example 1566-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylicacid Example 156A (3-bromo-2-methyl-phenyl)-methyl-phenyl-amine

1,3-Dibromo-2-methylbenzene (5.01 g) and N-methylaniline (1.00 g) wereadded to toluene (65 mL). The solution was degassed and flushed withnitrogen three times. Cesium carbonate (9.12 g),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.872 g), and palladium(II) acetate (0.314 g) were added. The solution was degassed and flushedwith nitrogen and then heated to 85° C. for 72 hours. The solution wascooled, added to 1 M aqueous HCl, and extracted with diethyl ether. Theextract was washed with brine, dried on anhydrous sodium sulfate,filtered, and concentrated under vacuum. The crude material was purifiedon silica gel using 2% ethyl acetate in hexanes.

Example 156B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 156A for EXAMPLE112A in EXAMPLE 112B.

Example 156C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 156B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(bs, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.65-7.57 (m, 1H), 7.55-7.23 (m,8H), 7.11 (m, 2H), 6.99 (m, 2H), 6.63 (t, 1H), 6.49 (d, 1H), 4.99 (bs,2H), 3.93 (t, 2H), 3.18 (s, 3H), 3.03 (t, 2H), 1.80 (s, 3H).

Example 1576-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 157A3,3-dimethyl-1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexanol

A solution of n-butyllithium (2.5 M, 12.48 mL) in tetrahydrofuran (40mL) was cooled to −78° C. and a solution of 1,5-dimethyl-1H-pyrazole(3.00 g) in tetrahydrofuran (3 mL) was added dropwise. After stirringfor 1 hour, a solution of 3,3-dimethylcyclohexanone (3.94 g) intetrahydrofuran (3 mL) was added dropwise and the reaction allowed towarm to 0° C. After stirring for 1 hour, the reaction was diluted withether (100 mL), washed with water (50 mL) and brine (50 mL), dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatographyeluting with a gradient of 3% to 25% ethyl acetate/hexanes provided thetitle compound.

Example 157B1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexanol

The title compound was prepared by substituting EXAMPLE 157A for EXAMPLE63B in EXAMPLE 63C.

Example 157C4-bromo-1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-pyrazole

A solution of EXAMPLE 157B (0.62 g) was dissolved inN,N-dimethylformamide (10 mL) and treated with NaH (0.062 g, 60% inmineral oil). After 10 minutes, iodomethane (0.16 mL) was added. After 1hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5 eq.) wereadded and stirring was continued at room temperature for 3 hours. Thereaction was diluted with ether (75 mL) and washed with water (50 mL)and brine (50 mL), dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography eluting with a gradient of 1.5%to 15% ethyl acetate/hexanes provided the title compound.

Example 157D1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 157C for EXAMPLE84C in EXAMPLE 84D.

Example 157E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

A solution of a 1:1 ratio of 1,4-dioxane and water was degassed withnitrogen for 45 minutes. This solution (5 mL) was added to EXAMPLE 1D(0.375 g), EXAMPLE 157D (0.30 g), potassium phosphate (0.62 g),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.021 g) and1,3,5,7-tetramethyl-6-tetradecane-2,4,8-trioxa-6-phosphaadamantane(0.034 g), degassed then heated to 90° C. under nitrogen for 4 hours.The reaction mixture was cooled, diluted with ether (75 mL) and washedwith water (3×50 mL) and brine (50 mL), dried over magnesium sulfate,filtered, and concentrated. Silica gel chromatography eluting with agradient of 10% to 50% ethyl acetate/hexanes gave the desired ester. Theester was dissolved in dichloromethane (1 mL) and TFA was added (1 mL)and the mixture was stirred overnight. The reaction mixture wasconcentrated, loaded onto silica gel and eluted with a gradient of 0.5%to 4% methanol/dichloromethane to provide the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 12.88 (s, 1H), 8.04 (d, 1H), 7.79(d, 1H), 7.62 (d, 1H), 7.53-7.41 (m, 3H), 7.41-7.32 (m, 2H), 7.28 (s,1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.98 (s, 2H), 3.89 (t, 2H), 3.15 (s,3H), 3.01 (t, 2H), 2.12 (s, 3H), 1.77-1.00 (m, 8H), 0.97 (s, 3H), 0.84(s, 3H).

Example 1586-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylicacid Example 158A(1S,2R,5S)-2-(azidomethyl)-6,6-dimethylbicyclo[3.1.1]heptane

((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methanol (500 mg) wasdissolved in dichloromethane (15 mL). The solution was chilled in an icebath and triethylamine (0.633 mL) was added, followed by methanesulfonylchloride (0.278 mL). The reaction was stirred for 2 hours at 0° C., andwas transferred to a separatory funnel and washed with 1N aqueous HCl(15 mL), saturated aqueous NaHCO₃ (20 mL) and brine (15 mL), then dried(Na₂SO₄), filtered and concentrated to give a crude oil, which wasdissolved in N,N-dimethylformamide (7.5 mL). Sodium azide (1054 mg) wasadded and the mixture was heated to 110° C. for 1.5 hours, and wascooled and partitioned between water (30 mL) and ethyl acetate (3×25mL). The organic extracts were washed with brine (25 mL), dried(Na₂SO₄), filtered, and concentrated to give a crude oil, which waspurified by flash chromatography on silica gel eluting with 50 to 100%dichloromethane in hexanes to provide the title compound.

Example 158B1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole

EXAMPLE 158A (200 mg), tributyl-n-propynyltin (367 mg) and toluene (1mL) were combined in a sealed reaction vessel which was heated to 130°C. overnight. The reaction mixture was placed atop a column and purifiedby flash chromatography on silica gel eluting with 0 to 20% ethylacetate in hexanes to provide the title compound.

Example 158C methyl 6-amino-3-bromopicolinate

To a solution of 6-amino-3-bromopicolinic acid (30 g) in ethyl acetate(300 mL) and methanol (300 mL) was added TMS-diazomethane (70 mL, 2M inhexanes) and the reaction mixture was stirred for 3 days. The mixturewas concentrated, taken up in ether (500 mL) and washed with aqueoussaturated Na₂CO₃ solution (twice) and brine, then dried over sodiumsulfate, filtered and concentrated to provide the title compound.

Example 158D methyl 3-bromo-6-fluoropicolinate

To a solution of nitrosonium terafluoroborate (17.8 g) indichloromethane (100 mL) at 5° C. was added EXAMPLE 158C (26.1 g) indichloromethane (250 mL) over 1 hour. The reaction mixture was stirredan for additional 30 minutes at 5° C., and then allowed to warm to roomtemperature overnight. The reaction mixture was quenched with pH 7buffer (100 mL), and then neutralized with solid potassium carbonate.The resulting mixture was extracted with ether (twice), and the combinedextracts were washed with brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by flash chromatography on silicagel eluting with 1 to 10% ethyl acetate in hexanes to provide the titlecompound.

Example 158E methyl3-(1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-1,2,3-triazol-4-yl)-6-fluoropicolinate

EXAMPLE 158B (75 mg), EXAMPLE 158D (35 mg) and PdCl₂(PPh₃)₂ (8.8 mg)were combined in a sealed tube with N,N-dimethylformamide (0.6 mL) andthe mixture was sparged with nitrogen and then heated to 100° C.overnight. Saturated aqueous KF (2 mL) and ethyl acetate (2 mL) wereadded and the mixture was stirred for 1 hour, then filtered throughdiatomaceous earth, rinsing the filter cake with ethyl acetate (15 mL).The layers were separated and the aqueous layer was extracted with ethylacetate (2×15 mL). The extracts were dried (Na₂SO₄), filtered andconcentrated, then purified by flash chromatography on silica gel using0 to 50% ethyl acetate in hexanes to provide the title compound.

Example 158F methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(((1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

EXAMPLE 1B (30 mg), EXAMPLE 158E (25 mg) and cesium carbonate (26.0 μL)were combined in DMSO (336 μL) and the mixture was heated to 65° C.overnight. The reaction mixture was then partitioned between ethylacetate (3×10 mL) and water (10 mL). The extracts were dried (Na₂SO₄),filtered, and concentrated, then purified by flash chromatography using0 to 50% ethyl acetate in hexanes to provide the title compound.

Example 158G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[(1S,2R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]methyl}-5-methyl-1H-1,2,3-triazol-4-yl)pyridine-2-carboxylicacid

EXAMPLE 158F (18 mg) was dissolved in dioxane (1 mL) and 1M aqueous LiOH(0.2 mL) was added. The reaction was heated to 60° C. for 3 hours, thencooled to room temperature, diluted with 1N aqueous HCl (5 mL) andextracted with ethyl acetate (3×10 mL). The organic extracts were dried(Na₂SO₄), filtered, and concentrated. The residue was purified by flashchromatography using 0 to 10% methanol in dichloromethane, to providethe title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm12.65-12.94 (br m, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.60-7.67 (m, 2H),7.41-7.51 (m, 2H), 7.31-7.40 (m, 2H), 6.99 (d, 1H), 4.99 (s, 2H),4.16-4.31 (m, 2H), 3.92 (t, 2H), 3.02 (t, 2H), 2.22-2.35 (m, 1H), 2.18(s, 3H), 1.77-1.96 (m, 4H), 1.69-1.76 (m, 1H), 1.49-1.63 (m, 1H), 1.18(s, 3H), 1.13 (s, 3H), 0.88 (d, 1H).

Example 1596-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid Example 159A(3-Bromo-2-methyl-phenyl)-(3,3-dimethyl-cyclohexyl)-amine

3-Bromo-2-methylaniline (1000 mg) and 3,3-dimethylcyclohexanone (780 mg)were added to dichloromethane (25 mL) and the mixture was stirred atroom temperature for 15 minutes. Sodium triacetoxyborohydride (1367 mg)was then added and the solution was stirred at room temperature for 16hours. Additional 3,3-dimethylcyclohexanone (780 mg) and sodiumtriacetoxyborohydride (1367 mg) were added, and the mixture was stirredfor another 16 hours. The mixture was then washed with a saturatedsodium bicarbonate solution and brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The crude material waspurified on silica gel using 2.5% ethyl acetate in hexanes to providethe title compound.

Example 159B(3-Bromo-2-methyl-phenyl)-(3,3-dimethyl-cyclohexyl)-methyl-amine

EXAMPLE 159A (400 mg), methyl iodide (230 mg), and potassium carbonate(224 mg) were added to N,N-dimethylformamide (5 mL) and the mixture wasstirred at room temperature for 16 hours. The mixture was added to waterand extracted with diethyl ether. The organic extract was washed withbrine, dried over anhydrous sodium sulfate, and filtered. The solventwas removed under vacuum to provide the title compound without furtherpurification.

Example 159C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 159B for EXAMPLE112A in EXAMPLE 112B.

Example 159D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 159C for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.90(bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.52-7.43 (m, 4H),7.38 (m, 3H), 7.06-6.95 (m, 2H), 5.00 (bs, 2H), 3.93 (t, 2H), 3.03 (t,2H), 2.15-1.92 (m, 3H), 1.74-1.50 (m, 2H), 1.48-1.15 (m, 5H), 1.10-0.75(m, 11H).

Example 1606-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 160A ethyl 1-morpholinocyclohexanecarboxylate

Ethyl 1-aminocyclohexancarboxylate hydrogen chloride (5.800 g),triethylamine (13.62 mL) and 1-bromo-2-(2-bromoethoxy)ethane (4.21 mL)were stirred together in N,N-dimethylformamide (50 mL) at 95° C.overnight. The reaction mixture was diluted with ethyl acetate (150 mL),washed with water (100 mL) and brine (100 mL), dried over magnesiumsulfate, filtered, and concentrated. Silica gel chromatography elutingwith a gradient of 5% to 25% ethyl acetate/hexanes provided the titlecompound.

Example 160B (1-morpholinocyclohexyl)methanol

The title compound was prepared by substituting EXAMPLE 160A for ethyl4,4-difluorocyclohexanecarboxylate in EXAMPLE 73A.

Example 160C 4-(1-((1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine

The title compound was prepared by substituting EXAMPLE 160B for(3-(dimethylamino)phenyl)methanol and 1H-pyrazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 160D4-(1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine

The title compound was prepared by substituting EXAMPLE 160C for EXAMPLE63A in EXAMPLE 63B.

Example 160E4-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyl)morpholine

The title compound was prepared by substituting EXAMPLE 160D for EXAMPLE63B in EXAMPLE 63C.

Example 160F tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((1-morpholinocyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 160E for EXAMPLE77D in EXAMPLE 77E.

Example 160G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 160F for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,2H), 9.50 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.57-7.41(m, 4H), 7.41-7.30 (m, 2H), 6.98 (d, 1H), 4.97 (s, 2H), 4.59 (s, 1H),4.10-3.51 (m, 8H), 2.95 (m, 6H), 2.42-2.03 (m, 4H), 2.00-0.97 (m, 8H).

Example 1616-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methy)amino]-methyl-3′-methyl-34′-bipyridine-2-carboxylicacid Example 161A N-cyclohexyl-4-iodo-N,3-dimethylpyridin-2-amine

2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylcyclohexanamine(2.2 ml) was heated at 180(C in a Biotage Initiator microwave reactorfor 18 hours. The reaction mixture was loaded onto a silica gelcartridge, and was eluted with 0-100% dichloromethane in hexanes toprovide the title compound.

Example 161B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-(cyclohexyl(methyl)amino)-3′-methyl-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 161A for EXAMPLE12A in EXAMPLE 112B.

Example 161C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 161B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.90 (s,1H), 8.07 (d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.44-7.51(m, 2H), 7.32-7.42 (m, 2H), 7.10 (d, 1H), 7.03 (d, 1H), 5.05 (s, 2H),3.97 (t, 2H), 3.44 (t, 1H), 3.05 (t, 2H), 2.96 (s, 3H), 2.06 (s, 3H),1.69 (d, 7H), 1.31 (d, 2H), 1.12 (q, 1H)

Example 162N-(1,3-benzothiazol-2-yl)-2-(5-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

A solution of EXAMPLE 157E (0.051 g), methanesulfonamide (0.015 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride.HCl(0.037 g) and 4-dimethylaminopyridine (0.019 g) were stirred together indichloromethane (1 mL) at room temperature overnight. The reactionmixture was loaded onto silica gel and eluted using a gradient of 0.5%to 3.25% methanol/dichloromethane to provide the title compound. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s, 1H), 11.81 (s, 1H), 8.03(d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.41 (m, 3H), 7.41-7.32 (m,2H), 7.29 (s, 1H), 7.00 (d, 1H), 4.96 (s, 2H), 4.00 (d, 2H), 3.93 (t,2H), 3.16 (s, 3H), 3.11 (s, 3H), 3.03 (t, 2H), 2.13 (s, 3H), 1.71 (d,1H), 1.58-1.00 (m, 7H), 0.96 (s, 3H), 0.84 (s, 3H).

Example 1636-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 163A2-(tert-butoxycarbonyl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxylicacid

To a solution of2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid(2.25 g) and tetramethylethylenediamine (1.347 mL) in tetrahydrofuran(40 mL) was added dropwise t-butyllithium (1.6M, 15.21 mL) at −78° C.The mixture was stirred at −78° C. for 40 minutes. To the resultingmixture was added iodomethane (5.07 mL) dropwise and the mixture wasstirred at −78° C. for 3 hours, followed by stirring at room temperatureovernight. The reaction mixture was quenched with saturated ammoniumchloride. The reaction mixture was extracted with ethyl acetate (150mL), and the organic layer was washed with brine (40 mL×3), dried overNa₂SO₄, filtered, and concentrated. The crude product was purified byflask chromotography (silica gel, 10% methanol/dichloromethane).

Example 163B tert-butyl8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of EXAMPLE 163A (400 mg),benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (714mg), triethylamine (0.383 mL) and benzo[d]thiazol-2-amine (247 mg) indichloromethane (10 mL) was stirred overnight at room temperature. Themixture was diluted with ethyl acetate (100 mL), washed with brine (30mL×3), dried over Na₂SO₄, filtered, concentrated and purified by flashchromotography (silica gel, petroleum ether/ethyl acetate=1/1).

Example 163CN-(benzo[d]thiazol-2-yl)-1-methyl-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

A solution of EXAMPLE 163B (150 mg) in dichloromethane (10 mL) wastreated with TFA (1 mL). The reaction mixture was stirred for 2 hours at30° C. The reaction mixture was diluted with ethyl acetate (100 mL),washed with saturated aqueous NaHCO₃, brine, dried over Na₂SO₄,filtered, and concentrated. The crude product was purified by flashchromotography (silica gel, dichloromethane/methanol=10/1).

Example 163D methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

A solution of EXAMPLE 163C (1 g), methyl 3-bromo-6-fluoropicolinate(0.715 g) and triethylamine (0.775 mL) in 12 mL DMSO was heated at 70°C. overnight followed by heating at 105° C. for 4 hours. The reactionmixture was diluted with ethyl acetate, washed three times with waterand brine, dried over Na₂SO₄, filtered, and concentrated. The productwas purified by flash chromotography (silica gel, 5-25% ethylacetate/hexanes).

Example 163E methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((1-methylcyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 163D for EXAMPLE77D and EXAMPLE 82D for EXAMPLE 30A in EXAMPLE 77E.

Example 163F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(1-methylcyclohexyl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 163E for EXAMPLE75B in EXAMPLE 75C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm13.02-12.79 (m, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.54 (d, 1H), 7.52 (d,1H), 7.50-7.42 (m, 2H), 7.40-7.32 (m, 2H), 7.28 (s, 1H), 6.86 (d, 1H),6.06 (q, 1H), 4.06-3.94 (m, 1H), 3.86 (s, 2H), 3.65 (dt, 1H), 3.14-3.01(m, 2H), 2.12 (s, 3H), 1.58-1.33 (m, 10H), 1.33-1.18 (m, 3H), 0.85 (s,3H).

Example 1646-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylicacid Example 164A 2-(cyclohexyl(methyl)amino)-4-iodonicotinonitrile

The title compound was prepared by substituting2-fluoro-4-iodonicotinonitrile for 2-fluoro-4-iodo-3-methylpyridine inEXAMPLE 161A.

Example 164B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3′-cyano-2′-(cyclohexyl(methyl)amino)-3,4′-bipyridine-2-carboxylate

The title compound was prepared by substituting EXAMPLE 164A for EXAMPLE112A in EXAMPLE 112B.

Example 164C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 164B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.90 (s,1H), 8.07 (d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.44-7.51(m, 2H), 7.33-7.42 (m, 2H), 7.10 (d, 1H), 7.03 (d, 1H), 5.05 (s, 2H),3.97 (t, 2H), 3.44 (t, 1H), 3.05 (t, 2H), 2.96 (s, 3H), 2.06 (s, 3H),1.54-1.84 (m, 7H), 1.21-1.42 (m, 2H), 1.06-1.19 (m, 1H).

Example 1656-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxycyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 165A 1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexanol

To a cold (−78° C.) solution of n-butyllithium (25 mL, 2.5M) intetrahydrofuran (30 mL) was added 1,5-dimethyl-1H-pyrazole (5.0 g) intetrahydrofuran (20 mL) dropwise via syringe. After 1 hour,cyclohexanone (5.1 g) in tetrahydrofuran (20 mL) was added dropwise andthe reaction mixture was allowed to warm to room temperature. Themixture was quenched by the addition of saturated ammonium chloridesolution and ethyl acetate. The layers were separated and the aqueouslayer was extracted with additional ethyl acetate (twice). The combinedorganics were dried over Na₂SO₄, filtered, and concentrated to providethe crude title compound.

Example 165B 1-((1-methoxycyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting CH₃I for1-bromo-2-methoxyethane and EXAMPLE 165A for EXAMPLE 151B in EXAMPLE151C.

Example 165C 4-iodo-1-((1-methoxycyclohexyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 165B for EXAMPLE65E in EXAMPLE 65F.

Example 165D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxycyclohexyl)methyl]-5-methyl-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 165C for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H),8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.40 (m, 5H), 7.27 (s, 1H),6.94 (d, 1H), 4.95 (s, 2H), 4.03 (m, 2H), 3.89 (t, 2H), 3.15 (m, 3H),3.01 (t, 2H), 2.12 (s, 3H), 1.36 (m, 10H)

Example 1666-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}pyridine-2-carboxylicacid Example 166A 5,5-dimethyl-1-oxaspiro[2.5]octane

The title compound was prepared by substituting3,3-dimethylcyclohexanone for cyclohexanone in EXAMPLE 101A.

Example 166B 1-(azidomethyl)-3,3-dimethylcyclohexanol

EXAMPLE 166A (1.93 g), ammonium chloride (3.68 g) and sodium azide (4.47g) were combined in a flask with methanol (40 mL) and water (16 mL) andthe mixture was heated to reflux overnight, then cooled to roomtemperature, diluted with water (200 mL) and extracted with ethylacetate (3×100 mL). The organic extracts were dried (Na₂SO₄), filtered,and concentrated. The crude material was purified by flashchromatography on silica gel using 0 to 10% ethyl acetate in hexanes toprovide the title compound.

Example 166C 1-(azidomethyl)-1-methoxy-3,3-dimethylcyclohexane

A solution of EXAMPLE 166B (1.33 g) was added dropwise to a suspensionof NaH (60% dispersion in mineral oil, 435 mg) in tetrahydrofuran (15mL) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 30minutes at room temperature. CH₃I (1.55 g) was added dropwise. Theresulting reaction mixture was stirred overnight at room temperature,and then quenched with water (100 mL) and extracted with ethyl acetate(3×50 mL). The extracts were washed with brine, dried (Na₂SO₄), andfiltered. After concentration, the crude material was purified by flashchromatography on silica gel using 0 to 7% ethyl acetate in hexanes toafford the title compound.

Example 166D1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)-5-methyl-4-(tributylstannyl)-1H-1,2,3-triazole

The title compound was prepared by substituting EXAMPLE 166C for EXAMPLE158A in EXAMPLE 158B.

Example 166E tert-butyl 3-bromo-6-fluoropicolinate

The title compound was prepared by substituting3-bromo-6-fluoropicolinic acid for 3-bromo-6-chloropicolinic acid inEXAMPLE 1C.

Example 166F tert-butyl6-fluoro-3-(1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 166D for EXAMPLE158B and EXAMPLE 166E for EXAMPLE 158D in EXAMPLE 158E.

Example 166G tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1-methoxy-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-1,2,3-triazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 166F for EXAMPLE158E in EXAMPLE 158F.

Example 166H6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(1-methoxy-3,3-dimethylcyclohexyl)methyl]-5-methyl-1H-1,2,3-triazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 166G for EXAMPLE88 in EXAMPLE 8C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 12.85 (s, 1H),12.64-12.81 (br s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.66 (d, 1H), 7.62(d, 1H), 7.42-7.51 (m, 2H), 7.32-7.41 (m, 2H), 7.01 (d, 1H), 5.00 (s,2H), 4.25 (s, 2H), 3.93 (t, 2H), 3.22 (s, 3H), 3.03 (t, 2H), 2.18 (s,3H), 1.66 (d, 1H), 1.28-1.56 (m, 4H), 1.02-1.24 (m, 3H), 0.96 (s, 3H),0.86 (s, 3H).

Example 1676-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({1-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 167A1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexanol

To a solution of EXAMPLE 165B (10.6 g) in N,N-dimethylacetamide (30 mL)was added N-bromosuccinimide (9.72 g). The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (400mL) and washed with aqueous sodium bisulfite, water, and brine.Evaporation of the solvent gave the crude product which was used in thenext reaction without further purification.

Example 167B1-((1-(allyloxy)cyclohexyl)methyl)-4-bromo-5-methyl-1H-pyrazole

The title compound was prepared by substituting allyl bromide for1-bromo-2-methoxyethane and EXAMPLE 167A for EXAMPLE 151B in EXAMPLE151C.

Example 167C1-((1-(allyloxy)cyclohexyl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of EXAMPLE 167B (1.25 g) in dioxane (30 mL) was addedPdCl₂ (40 mg), S-Phos (0.328 g), pinacolborane (0.77 g) andtriethylamine (1.22 g). The mixture was stirred at reflux under nitrogenfor 3 hours. The reaction mixture was diluted with ethyl acetate (200mL), washed with water and brine, dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Flash column purification (20%ethyl acetate in hexane) provided the title compound.

Example 167D tert-butyl3-(1-((1-(allyloxy)cyclohexyl)methyl)-5-methyl-1H-pyrazol-4-yl)-6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate

The title compound was prepared by substituting EXAMPLE 167C for EXAMPLE30A and EXAMPLE 1D for EXAMPLE 75A in EXAMPLE 75B.

Example 167E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((1-(2,3-dihydroxypropoxy)cyclohexyl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

To a stirred solution of EXAMPLE 167D (600 mg) and N-methylmorpholineoxide (489 mg) in 50% aqueous dioxane (10 mL) was added a solution ofosmium tetraoxide (1.2 mL, 0.12 M in t-butanol). After stirring for 1hour, ethyl acetate was added followed by saturated sodium bisulfite.The reaction mixture was stirred for 20 minutes. The organic layer wasseparated and the aqueous layer was extracted with ethyl acetate (3×100mL). The combined organic layers were dried (anhydrous Na₂SO₄),filtered, and concentrated under vacuum to give the crude product.

Example 167F tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((1-(2-oxoethoxy)cyclohexyl)methyl)-1H-pyrazol-4-yl)picolinate

A solution of EXAMPLE 167E (600 mg) in acetone (30 mL) was treated witha solution of sodium periodate (852 mg) in water (5 mL). After about 4hours, the solvent was removed by distillation and the residue wasextracted with ethyl acetate (3×100 mL). The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated under reducedpressure to give crude product which was purified by flash columnchromatography (20% ethyl acetate in hexane) to give the pure product.

Example 167G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({1-[2-(1,1-dioxidothiomorpholin-4-yl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

To a solution of EXAMPLE 167F (72 mg) and thiomorpholine 1,1-dioxide(13.5 mg) in dichloromethane (3 mL) was added sodiumtriacetoxyborohydride (32 mg). The mixture was stirred overnight. Themixture was dissolved in ethyl acetate (200 mL) and washed with 2Naqueous NaOH and brine, and dried over Na₂SO₄. Filtration andevaporation of the solvent gave crude product which was dissolved indichloromethane (2 mL) and TFA (2 mL). After stirring overnight, thesolvent was evaporated. The residue was purified by reverse phasechromatography using a Gilson system, eluting with 20-80% acetonitrilein 0.1% TFA water solution to provide the title compound. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d,1H), 7.62 (d, 1H), 7.42 (m, 5H), 6.97 (d, 1H), 4.96 (s, 2H), 4.10 (s,3H), 3.53 (m, 8H), 3.02 (t, 2H), 2.13 (s, 3H), 1.43 (m, 10H).

Example 1686-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 168A ethyl 4-iodo-5-methyl-1H-pyrrole-2-carboxylate

The title compound was prepared by substituting with ethyl5-methyl-1H-pyrrole-2-carboxylate for EXAMPLE 65E in EXAMPLE 65F.

Example 168B 4-iodo-5-methyl-1H-pyrrole-2-carboxylic acid

EXAMPLE 168A (1 g) in tetrahydrofuran (30 mL) and methanol (10 mL) wastreated with 2 N aqueous NaOH (20 mL) overnight. The reaction mixturewas cooled to 0° C., acidified to pH 5, diluted with water (30 mL) andconcentrated to remove the organic solvent. The precipitates werecollected by filtration, washed with water and dried under vacuum toprovide the title compound.

Example 168C 4-iodo-5-methyl-1H-pyrrole-2-carboxamide

To a solution of EXAMPLE 168B (7.7 g) in tetrahydrofuran (20 mL) at 0°C. was added carbonyldiimidazole (14.9 g). The resulting mixture wasstirred at room temperature for 2 hours. The reaction mixture was cooledto 0° C. and ammonium hydroxide (3 mL) was added. The mixture wasstirred at room temperature for 2 hours and concentrated. The residuewas dissolved in ethyl acetate, washed with brine and concentrated toprovide the title compound.

Example 168D 4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

To a solution of EXAMPLE 168C (300 mg) in N,N-dimethylformamide (6 mL)and pyridine (0.6 mL) at 0° C. was added dropwise oxalyl chloride (0.35mL). The mixture was stirred at room temperature for 30 minutes, dilutedwith ethyl acetate and washed with saturated NaHCO₃ and waterextensively. The organic layer was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by flash chromatography, andeluted with dichloromethane to provide the title compound.

Example 168E4-iodo-5-methyl-1-((1-morpholinocyclohexyl)methyl)-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 160B for(3-(dimethylamino)phenyl)methanol and EXAMPLE 168D for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 168F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-2-methyl-1-{[1-(morpholin-4-yl)cyclohexyl]methyl}-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 168E for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 88 inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41 (m, 5H), 6.95 (d, 1H),6.83 (s, 1H), 4.96 (s, 2H), 4.01 (m, 2H), 3.89 (t, 2H), 3.01 (t, 2H),2.69 (m, 3H), 2.10 (s, 3H), 1.95 (m, 3H), 1.56 (m, 3H), 1.27 (m, 4H),0.96 (m, 3H).

Example 1696-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-hydroxyethoxy)cyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

To a solution of EXAMPLE 167F (56 mg) in tetrahydrofuran (10 mL) wasadded NaBH₄ (15 mg). The mixture was stirred at room temperatureovernight. The mixture was added to ethyl acetate (200 mL) and water (60mL). The organic layer was washed with brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave crude product which wasdissolved in dichloromethane (2 mL) and TFA (2 mL). After sitting on thebench overnight, the solvent was evaporated. The residue was purified byreverse phase chromatography using a Gilson system, eluting with 20-80%acetonitrile in 0.1% TFA water solution to provide the desired product.¹H NMR (300 MHz, dimethylsulfoxide-dc) 3 ppm 12.85 (s, 1H), 8.03 (d,1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.29 (s, 1H), 6.95 (d,1H), 4.95 (s, 2H), 4.04 (s, 3H), 3.49 (m, 3H), 3.01 (t, 2H), 2.14 (m,3H), 1.37 (m, 11H).

Example 1706-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dimethoxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 170A 1-((5-methyl-1H-pyrazol-1-yl)methyl)cycloheptanol

The title compound was prepared by substituting cycloheptanone forcyclohexanone in EXAMPLE 165A.

Example 170B 1-((1-(allyloxy)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting allyl bromide for1-bromo-2-methoxyethane and EXAMPLE 170A for EXAMPLE 151B in EXAMPLE151C.

Example 170C3-(1-((5-methyl-1H-pyrazol-1-yl)methyl)cycloheptyloxy)propane-1,2-diol

To a stirred solution of EXAMPLE 170B (248 mg) and N-methylmorpholineoxide (586 mg) in 50% aqueous dioxane (10 mL) was added a solution ofosmium tetraoxide (1 mL, 0.12 M). After stirring for 3 hours, ethylacetate was added followed by saturated sodium bisulfite. The reactionmixture was stirred for 20 minutes. The organic layer was separated andthe aqueous layer was extracted with ethyl acetate (3×60 mL). Thecombined organic layers were dried (anhydrous Na₂SO₄), filtered, andconcentrated under vacuum to give the crude product.

Example 170D1-((1-(2,3-dimethoxypropoxy)cycloheptyl)methyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting methyl iodide for1-bromo-2-methoxyethane and EXAMPLE 170C for EXAMPLE 151B in EXAMPLE151C.

Example 170E1-((1-(2,3-dimethoxypropoxy)cycloheptyl)methyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 170D for EXAMPLE65E in EXAMPLE 65F.

Example 170F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dimethoxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 170E for EXAMPLE75A in EXAMPLE 758, and then substituting that product for EXAMPLE 88 inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41 (m, 5H), 7.27 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 4.04 (m, 3H), 3.89 (t, 2H), 3.44 (d, 2H),3.35 (m, 4H), 3.28 (s, 3H), 3.19 (m, 3H), 3.00 (t, 2H), 2.14 (s, 3H),1.51 (m, 14H).

Example 171N-(1,3-benzothiazol-2-yl)-2-{5-[5-cyano-4-(cyclohexylmethyl)-2-methyl-1H-pyrrol-3-yl]-6-[(methylsulfonyl)carbamoyl]pyridin-2-yl}-1,2,3,4-tetrahydroisoquinoline-8-carboxamide

1-Ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (34.6mg), 4-dimethylaminopyridine (55.2 mg), EXAMPLE 130G (95 mg), andmethanesulfonamide (17.19 mg) in dichloromethane (2 mL) was stirredovernight and concentrated. The residue was purified by reverse phasechromatography, and eluted with 40-80% acetonitrile in 0.1% TFA watersolution to provide the desired product. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 11.81 (s, 1H), 8.03 (d, 1H),7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.54 (m, 3H), 7.33-7.40 (m, 2H), 7.00(d, 1H), 6.80 (s, 1H), 4.97 (s, 2H), 3.94 (t, 2H), 3.83 (d, 2H), 3.13(s, 3H), 3.03 (t, 2H), 2.09 (s, 3H), 1.49-1.74 (m, 6H), 1.09-1.26 (m,3H), 0.92-1.05 (m, 2H).

Example 1726-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 172A1-((1-hydroxycycloheptyl)methyl)-5-methyl-1H-pyrrole-2-carbonitrile

1-Oxaspiro[2,6]nonane (2.5 g), 5-methyl-1H-pyrrole-2-carbonitrile (2.1g) and Cs₂CO₃ (6.45 g) in N,N-dimethylformamide (15 mL) was heated at120° C. in a Biotage Initiator microwave reactor for 30 minutes. Thereaction mixture was diluted with ethyl acetate, washed with water andconcentrated. The residue was purified by reverse phase chromatography,and was eluted with 30%-70% acetonitrile in 0.1% TFA water solution toprovide the title compound.

Example 172B1-((1-(2-methoxyethoxy)cycloheptyl)methyl)-5-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 172A for EXAMPLE151B in EXAMPLE 151C.

Example 172C4-bromo-1-((1-(2-methoxyethoxy)cycloheptyl)methyl)-5-methyl-1H-pyrrole-2-carbonitrile

EXAMPLE 172B (218 mg) in acetonitrile (10 ml) was treated withN-bromosuccinimide (140 mg) for 15 minutes and concentrated. The residuewas purified by flash chromatography, and was eluted with 0-100% hexanesin dichloromethane to provide the title compound.

Example 172D methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-bromopicolinate

The title compound was prepared by substituting methyl3-bromo-6-fluoropicolinate for EXAMPLE 1C in EXAMPLE 1D.

Example 172E methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinate

The title compound was prepared by substituting EXAMPLE 172D for EXAMPLE63C in EXAMPLE 63D.

Example 172F methyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-cyano-1-((1-(2-methoxyethoxy)cycloheptyl)methyl)-2-methyl-1H-pyrrol-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 172E for EXAMPLE30A and EXAMPLE 172C for EXAMPLE 112A in EXAMPLE 112B.

Example 172G6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(2-methoxyethoxy)cycloheptyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

EXAMPLE 172F (50 mg) in tetrahydrofuran (5 mL) and methanol (3 mL) wastreated with 2 N aqueous NaOH (3 mL) overnight, acidified to pH 1, andconcentrated. The residue was suspended in water and the precipitateswere collected, washed with water and dried over Na₂SO₄ to give thetitle compound. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41-7.50 (m, 3H),7.33-7.39 (m, 2H), 6.95 (d, 1H), 6.79 (s, 1H), 4.96 (s, 2H), 3.99 (s,2H), 3.89 (t, 2H), 3.44-3.51 (m, 2H), 3.21 (s, 2H), 3.01 (t, 2H), 2.12(s, 3H), 1.37-1.70 (m, 12H).

Example 1736-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(1,4-dioxan-2-ylmethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 173A1-((1-((1,4-dioxan-2-yl)methoxy)cycloheptyl)methyl)-5-methyl-1H-pyrazole

To a stirred solution of EXAMPLE 170C (315 mg) in dichloromethane (10mL) was added NaH (80 mg) at 0° C. The mixture was stirred for 10minutes. A solution of vinyl selenone (240 mg) in dichloromethane (5 mL)was added to the mixture and the mixture was stirred at room temperaturefor 3 hours. The mixture was quenched with aqueous NH₄Cl, extracted withdichloromethane (2×200 mL), washed with water and brine, and dried overNa₂SO₄. Filtration and evaporation of the solvent gave the crude productwhich was purified by column eluted with 50% ethyl acetate in hexane) toprovide the title compound.

Example 173B1-((1-((1,4-dioxan-2-yl)methoxy)cycloheptyl)methyl)-4-iodo-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 173A for EXAMPLE65E in EXAMPLE 65F.

Example 173C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(1,4-dioxan-2-ylmethoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 173B for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.27 (s, 1H),6.95 (d, 1H), 4.95 (s, 2H), 4.02 (m, 4H), 3.89 (m, 2H), 3.59 (m, 5H),3.42 (m, 3H), 3.02 (m, 2H), 2.13 (s, 3H), 1.33 (m, 14H)

Example 1746-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(morpholin-4-yl)-2-oxoethoxy]cyclohexyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 174A2-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyloxy)acetaldehyde

To a solution of EXAMPLE 167B (3.13 g) in dioxane/water (3:1, 40 mL) wasadded 2,6-lutidine (2.5 mL), OsO₄ (2.5% in tert-butanol, 2.75 mL), andNaIO₄ (8.55 g) under argon. The reaction mixture was stirred at roomtemperature for 4 hours, then water (50 mL) and dichloromethane (200 mL)were added. The organic layer was separated, and the water phase wasextracted by dichloromethane (3×200 mL). The combined organic layerswere washed with brine (200 mL) and dried over Na₂SO₄. After filtration,the solvent was removed to give the crude product which was used in thenext step without further purification.

Example 174B2-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyloxy)acetic acid

To a solution of EXAMPLE 174A (3.15 g) in t-butanol (200 mL) andtetrahydrofuran (50 mL) was added 2-methyl-2-butene (8 mL). The mixturewas allowed to stir in an ice bath. NaClO₂ (1.2 g) and NaH₂PO₄ (3 g)were dissolved into water (75 mL), and the solution was added to themixture. The mixture was allowed to stir in an ice bath for 15 minutes,and then stirred at room temperature for 12 hours. NH₄Cl was added, themixture was extracted with ethyl acetate, and the organic layer waswashed with brine, dried over anhydrous Na₂SO₄, filtered, andconcentrated to dryness to provide the title compound.

Example 174C2-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)cyclohexyloxy)-1-morpholinoethanone

To a solution of EXAMPLE 174B (331 mg) in dichloromethane (10 mL) wasadded morpholine (174 mg), 4-dimethylaminopyridine (122 mg) and1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (287 mg).The mixture was stirred overnight. The mixture was diluted with ethylacetate (200 mL) and washed with water and brine and dried over Na₂SO₄.Filtration and evaporation of the solvent gave the crude title compound.

Example 174D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[5-methyl-1-({1-[2-(morpholin-4-yl)-2-oxoethoxy]cyclohexyl}methyl)-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 174C for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (s, 1H),8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42 (m, 5H), 7.29 (s, 1H),6.96 (d, 1H), 4.95 (s, 2H), 4.09 (m, 4H), 3.89 (t, 2H), 3.01 (t, 2H),2.13 (s, 3H), 1.65 (m, 2H), 1.35 (m, 10H).

Example 1756-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dihydroxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 175A3-(1-((4-iodo-5-methyl-1H-pyrazol-1-yl)methyl)cycloheptyloxy)propane-1,2-diol

The title compound was prepared by substituting EXAMPLE 170C for EXAMPLE65E in EXAMPLE 65F.

Example 175B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2,3-dihydroxypropoxy)cycloheptyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 175A for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C, 134. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42 (m, 6H), 7.28 (s,1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.34 (m, 2H), 3.89 (m, 2H), 3.38 (m,6H), 3.13 (m, 4H), 3.01 (t, 2H), 2.13 (m, 3H), 1.43 (m, 12H).

Example 1766-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(dimethylamino)cyclohexyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid Example 176A (1-(dimethylamino)cyclohexyl)methanol

To a solution of (1-aminocyclohexyl)methanol (378 mg) in ethanol (10 mL)was added CH₃I (2.1 g) and NaHCO₃ (246 mg). The mixture was stirred for24 hours. The mixture was dissolved in 2N aqueous NaOH (20 mL) and ethylacetate (200 mL). The organic layer was dried over Na₂SO₄, filtered, andconcentrated under vacuum to give the crude title compound.

Example 176B1-((1-(dimethylamino)cyclohexyl)methyl)-4-iodo-5-methyl-1H-pyrrole-2-carbonitrile

The title compound was prepared by substituting EXAMPLE 176A for(3-(dimethylamino)phenyl)methanol and EXAMPLE 168D for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in EXAMPLE34A.

Example 176C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(5-cyano-1-{[1-(dimethylamino)cyclohexyl]methyl}-2-methyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 176B for EXAMPLE75A in EXAMPLE 75B, and then substituting that product for EXAMPLE 8B inEXAMPLE 8C. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H),8.75 (m, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5H),6.98 (d, 1H), 6.96 (s, 1H), 4.98 (s, 2H), 4.41 (s, 2H), 3.90 (t, 2H),2.99 (m, 8H), 2.13 (m, 3H), 1.31 (m, 10H).

Example 1776-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid Example 177A cyclohexanecarboxylic acid(3-bromo-2-methyl-phenyl)-methyl-amide

3-Bromo-N,2-dimethylaniline (150 mg) and diisopropylethylamine (291 mg)were added to dichloromethane (5 mL). Cyclohexanecarbonyl chloride (115mg) was added and the solution was stirred at room temperature for 16hours. The solution was diluted with ethyl acetate and washed two timeswith 1M aqueous HCl and once with brine. The solution was dried onanhydrous sodium sulfate, filtered, and the solvent was removed toprovide the title compound which was used without further purification.

Example 177B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 177A for EXAMPLE112A in EXAMPLE 112B.

Example 177C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 177B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 8.03 (d,1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.55-7.42 (m, 3H), 7.36 (q, 2H),7.28-7.18 (m, 2H), 7.07-7.01 (m, 2H), 5.00 (bs, 2H), 3.94 (t, 2H), 3.04(bs, 5H), 2.00 (m, 1H), 1.85 (bs, 3H), 1.65-1.35 (m, 6H), (m, 3H),1.11-0.99 (m, 2H), 0.96-0.80 (m, 2H).

Example 1786-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylsulfonyl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 178A4-bromo-1-((3,3-dimethyl-1-(2-(methylsulfonyl)ethoxy)cyclohexyl)methyl)-5-methyl-1H-pyrazole

To a solution of EXAMPLE 157B (0.218 g) in tetrahydrofuran (2.5 mL) wasadded sodium hydride (0.027 g) and the reaction mixture was stirred for15 minutes at room temperature. Methylsulfonylethene (0.095 mL) wasadded and the reaction was stirred at room temperature overnight. Thereaction was cooled and diluted with ethyl acetate (50 mL). The organiclayer was washed with water (50 mL) and brine (50 mL), dried overmagnesium sulfate, filtered, and concentrated. Silica gel chromatographyeluting with a gradient of 1-20% ethyl acetate in hexanes provided thetitle compound.

Example 178B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,3-dimethyl-1-(2-(methylsulfonyl)ethoxy)cyclohexyl)methyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 178A for EXAMPLE77D in EXAMPLE 77E.

Example 178C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-methylsulfonyl)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 178B for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 6 (s,2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.56-7.41 (m, 3H),7.40-7.33 (m, 2H), 7.32 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.16-3.96(m, 2H), 3.95-3.79 (m, 3H), 3.79-3.68 (m, 1H), 3.32 (d, 3H), 3.01 (t,2H), 2.94 (s, 3H), 2.14 (s, 3H), 1.74 (d, 1H), 1.52 (t, 2H), 1.45-1.27(m, 2H), 1.27-1.02 (m, 5H), 1.00 (s, 3H), 0.86 (s, 3H).

Example 1796-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylicacid Example 179A 1-Methyl-cyclohexanecarboxylic acid(3-bromo-2-methyl-phenyl)-methyl-amide

The title compound was prepared by substituting1-methylcyclohexanecarbonyl chloride for cyclohexanecarbonyl chloride inEXAMPLE 177A.

Example 179B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 179A for EXAMPLE112A in EXAMPLE 112B.

Example 179C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 179B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm (8.03,1H), 7.79 (d, 1H), 7.63 (d, 1H), 7.50-7.32 (m, 5H), 7.18 (m, 2H), 7.02(m, 2H), 4.99 (bs, 2H), 3.93 (t, 2H), 3.02 (bs, 5H), 1.91 (s, 3H),1.85-1.62 (m, 2H), 1.44-1.10 (m, 8H), 0.95 (m, 3H).

Example 1806-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)-3,3-dimethylcyclohhexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid Example 180A1-((1-(allyloxy)-3,3-dimethylcyclohexyl)methyl)-4-bromo-5-methyl-1H-pyrazole

To a solution of EXAMPLE 157B (2.73 g) in N,N-dimethylformamide (20 mL)was added NaH (1.45 g) and the reaction mixture was stirred for 30minutes at room temperature. 3-Bromoprop-1-ene (1.53 mL) was added andthe mixture was stirred at room temperature for 2 hours. The reactionmixture was diluted with diethyl ether (75 mL), washed with water (2×50mL) and brine (50 mL), dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography eluting with a gradient of 1.5%to 15% ethyl acetate/hexanes provided the title compound.

Example 180B2-(1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexyloxy)ethanol

A solution of EXAMPLE 180A (2.80 g) in dioxane/water (30 mL/10 mL) wasadded to 2,6-dimethylpyridine (1.909 mL) and sodium periodate (7.02 g)followed by the addition of osmium tetroxide (2.5% solution, 1.0 mL) andthe reaction mixture was stirred for 30 minutes at room temperature. Thereaction mixture was diluted with ethyl acetate (50 mL), washed withwater (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered,and concentrated. The residue was dissolved in methanol (20 mL) andsodium borohydride (0.16 g) was added. The mixture was stirred at roomtemperature for 1 hour. An aqueous work up followed by silica gelchromatography using 2-30% ethyl acetate in hexanes provided the titlecompound.

Example 180C4-bromo-1-((1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl)methyl)-5-methyl-1H-pyrazole

To a solution of EXAMPLE 180B (2.2 g) in N,N-dimethylformamide (20 mL)was added sodium hydride (0.38 g). After stirring for 30 minutes, methyliodide (0.60 mL) was added. The reaction mixture was stirred for 2 hoursat room temperature, diluted with ether (100 mL) and washed with water(2×75 mL) and brine (75 mL), dried over magnesium sulfate, filtered, andconcentrated. Silica gel chromatography eluting with a gradient of 3% to25% ethyl acetate/hexanes provided the title compound.

Example 180D1-((1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl)methyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 180C for EXAMPLE63C in EXAMPLE 63D.

Example 180E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-{[1-(2-methoxyethoxy)-3,3-dimethylcyclohexyl]methyl}-5-methyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 180D for EXAMPLE157D in EXAMPLE 157E. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.84(s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53-7.40 (m, 3H),7.36 (m, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.10-3.93 (m,2H), 3.89 (t, 2H), 3.62-3.45 (m, 4H), 3.23 (s, 3H), 3.01 (t, 2H), 2.12(s, 3H), 1.79 (d, 1H), 1.63-1.01 (m, 7H), 0.99 (s, 3H), 0.84 (s, 3H).

Example 1816-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridine-2-carboxylicacid Example 181A cyclohexanesulfonic acid methylamide

Cyclohexanesulfonyl chloride (500 mg) was added to methylamine (12.3 mL,2M solution in tetrahydrofuran) and the reaction mixture was stirred atroom temperature for one hour. The solution was added to 1M aqueous HCland extracted with ethyl acetate. The extract was washed with brine anddried over anhydrous sodium sulfate. After filtration, the solvent wasremoved under vacuum to yield the product.

Example 181B cyclohexanesulfonic acid(3-bromo-2-cyano-phenyl)-methyl-amide

2-Bromo-6-fluorobenzonitrile (500) mg), EXAMPLE 181A (487 mg), andpotassium carbonate (415 mg) were added to N,N-dimethylacetamide (15 mL)and the mixture was heated to 85° C. for three days. The mixture wascooled, added to 1M aqueous HCl, extracted with 70% ethyl acetate(hexanes), washed with water, washed with brine, and dried overanhydrous sodium sulfate. After filtration, the solvent was removedunder vacuum, and the crude material was recrystallized from ethylacetate to provide the title compound.

Example 181C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(ethyl)amino]phenyl}pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 181B for EXAMPLE112A in EXAMPLE 112B.

Example 181D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(ethyl)amino]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 181C for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (dd, 1H), 7.63 (d, 1H), 7.60(dd, 1H), 7.49-7.32 (m, 6H), 7.10 (d, 1H), 5.05 (bs, 2H), 3.98 (t, 2H),3.28 (s, 3H), 3.04 (t, 2H), 2.14 (d, 2H), 1.79 (d, 2H), 1.62 (d, 1H),1.51-1.10 (m, 6H).

Example 1826-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylicacid Example 182A2-(2-adamantan-1-yl-pyrrolidin-1-yl)-6-bromo-benzonitrile

2-Bromo-6-fluorobenzonitrile (900 mg), 2-adamantan-1-yl-pyrrolidine (924mg), and potassium carbonate (1244 mg) were added to dimethyl sulfoxideand the mixture was heated at 130° C. for 16 hours. The solution wascooled, diluted with ethyl acetate, washed twice with 1M HCl, washedwith brine, and dried over anhydrous sodium sulfate. After filtration,the crude material was concentrated under vacuum and purified on silicagel using 5% ethyl acetate (hexanes) to provide the title compound.

Example 182B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-cyano-3-{2-[tricyclo[3.3.1.1^(3,7)]dec-1-yl]pyrrolidin-1-yl}phenyl)pyridine-2-carboxylicacid tert-butyl ester

The title compound was prepared by substituting EXAMPLE 182A for EXAMPLE112A in EXAMPLE 112B.

Example 182C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 182B for EXAMPLE7D in EXAMPLE 7E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.85(bs, 1H), 12.68 (bs, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.65 (d, 1H), 7.62(d, 1H), 7.50-7.44 (m, 2H), 7.40-7.27 (m, 4H), 7.03 (d, 1H), 6.65 (d,1H), 5.02 (bs, 2H), 3.96 (m, 2H), 3.63 (m, 1H), 3.18 (m, 2H), 3.04 (t,2H), 1.91-1.82 (m, 5H), 1.68-1.42 (m, 12H), 1.24 (bs, 2H).

Example 1836-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylicacid Example 183A tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-2′-chloro-3′-methyl-3,4′-bipyridine-2-carboxylate

To a solution of EXAMPLE 30A (1.22 g) in dioxane (4 mL), and aqueousNaHCO₃ (2 mL) was added 2-chloro-4-iodo-3-methylpyridine (505 mg), andtetrakis(triphenylphosphine)palladium(0) (115 mg). The mixture wasstirred at 120° C. for 20 minutes in a Biotage Initiator microwavereactor. The mixture was diluted with ethyl acetate (300 mL) and washedwith water (3 times) and brine, and dried over Na₂SO₄. Filtration andevaporation of the solvent gave crude product which was loaded on asilica gel column and eluted with 20% ethyl acetate in dichloromethaneto provide the title compound.

Example 183B6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylicacid

To a solution of EXAMPLE 183A (200 mg) in N,N-dimethylacetamide (15 mL)was added piperidine (110 mg), K₃PO₄ (218 mg), andbis(tri-tert-butylphosphine)palladium (7.01 mg). The mixture was stirredat 100° C. overnight under nitrogen. The mixture was diluted with ethylacetate (300 mL), washed with water and brine, and dried over Na₂SO₄.Filtration and evaporation of the solvent gave crude product which waspurified by flash chromatography to give the pure ester which wasdissolved in dichloromethane/TFA (1:1, 6 mL) and stirred overnight. Thesolvent was evaporated under vacuum and the residue was dissolved inDMSO/methanol (1:1, 10 ml). The residue was purified by reverse phasechromatography using a Gilson system, eluting with 20-80% acetonitrilein 0.1% TFA water solution to provide the desired product. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ ppm 12.86 (s, 1H), 8.05 (m, 2H), 7.79 (d,1H), 7.48 (m, 5H), 7.05 (d, 1H), 6.87 (d, 1H), 5.02 (s, 2H), 3.95 (t,2H), 3.07 (m, 5H), 2.01 (s, 3H), 1.65 (m, 6H).

Example 1846-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 184A 3-cyclohexyl-3-(1H-pyrazol-1-yl)propan-1-ol

To a solution of EXAMPLE 152A (2.42 g) in toluene (20 mL)diisobutylaluminum hydride (28.2 mL) was added at −78° C. The reactionmixture was stirred for 60 minutes. The reaction mixture was quenchedwith methanol (10 mL), 1M aqueous HCl (200 mL) and washed with saturatedNaHCO₃. The organic layer was dried over magnesium sulfate, filtered andconcentrated. The product was purified by flash chromotography (silicagel, 10-100% ethyl acetate/hexanes) to provide the title compound.

Example 184B 1-(1-cyclohexyl-3-methoxypropyl)-1H-pyrazole

To a solution of EXAMPLE 184A (0.23 g) in dry tetrahydrofuran (5 mL) wasadded sodium hydride (0.166 g) at 0° C. The reaction mixture was stirredfor 60 minutes when methyl iodide (0.259 mL) was added and stirring wascontinued for 4 hours at room temperature. The reaction mixture wasquenched with ammonium chloride solution (5 mL), and extracted withethyl acetate. The organic layer was dried over magnesium sulfate,filtered and concentrated. The crude material was purified by flashchromatography on silica gel, and was eluted with 10-60% ethylacetate/hexanes.

Example 184C 1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 184B for EXAMPLE63A in EXAMPLE 63B.

Example 184D4-bromo-1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 184C for EXAMPLE63B in EXAMPLE 63C.

Example 184E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 184D for EXAMPLE77D in EXAMPLE 77E.

Example 184F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(1-cyclohexyl-3-methoxypropyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 184E for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.85 (s,1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52-7.40 (m, 3H),7.41-7.29 (m, 3H), 6.95 (d, 1H), 4.95 (s, 2H), 3.97-3.84 (m, 4H),3.15-3.07 (m, 1H), 3.10 (s, 3H), 3.01 (t, 2H), 2.64 (td, 1H), 2.16-2.05(m, 1H), 2.04 (s, 3H), 2.00-1.82 (m, 2H), 1.81-1.65 (m, 2H), 1.65-1.50(m, 2H), 1.29-0.75 (m, 6H).

Example 1856-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylamino)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid Example 185A3,3-dimethyl-1-((5-methyl-1H-pyrazol-1-yl)methyl)cyclohexanol

To a cold (−78° C.) solution of nBuLi (12.48 mL) in tetrahydrofuran (40mL) was added a solution of 1,5-dimethyl-1H-pyrazole (3.0 g) intetrahydrofuran (3 mL) dropwise. After stirring for 1 hour, a solutionof 3,3-dimethylcyclohexanone (3.94 g) in tetrahydrofuran (3 mL) wasadded dropwise, and the reaction was allowed to warm to 0° C. Afterstirring for 1 hour, the reaction mixture was diluted with ether (100mL), washed with water (50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated. Purification of the residue bysilica gel chromatography, eluting with a gradient of 3% to 25% ethylacetate in hexanes, gave the title compound.

Example 185B1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexanol

The title compound was prepared by substituting EXAMPLE 185A for EXAMPLE63B in EXAMPLE 63C.

Example 185C1-((1-(allyloxy)-3,3-dimethylcyclohexyl)methyl)-4-bromo-5-methyl-1H-pyrazole

To a cold (0° C.) solution of EXAMPLE 185B (3.63 g) inN,N-dimethylformamide (25 mL) was added NaH (0.964 g, 60% dispersion inmineral oil), and the reaction was stirred for 30 minutes.3-Bromoprop-1-ene (1.529 mL) was added. The cooling bath was removed,and the reaction was warmed to room temperature. The reaction mixturewas heated to 50° C., whereupon a significant evolution of gas occurred.After 2 hours, the reaction mixture was diluted with diethyl ether (75mL), washed with water (2×50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated. Purification of the residue bysilica gel chromatography, eluting with a gradient of 1.5% to 15% ethylacetate in hexanes, gave the title compound.

Example 185D 2-(trimethylsilyl)ethyl(2-((1-((4-bromo-5-methyl-1H-pyrazol-1-yl)methyl)-3,3-dimethylcyclohexyl)oxy)ethyl)(methyl)carbamate

To a solution of EXAMPLE 185C (0.93 g) in dioxane (9 mL) and water (3mL) was added 2,6-dimethylpyridine (0.634 mL) and sodium periodate(2.331 g) followed by osmium tetroxide (0.277 mL, 2.5% solution intert-butanol). The reaction mixture was stirred for 30 minutes at roomtemperature, whereupon a significant precipitate formed. The reactionmixture was stirred for an additional 1 hour, diluted with ether (100mL), washed with water (50 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and concentrated. To the residue dissolved inmethanol (5 mL) was added methanamine (1.635 mL) and sodiumcyanoborohydride (0.171 g). After 1 hour, the reaction mixture wasdiluted with ethyl acetate (50 mL), washed with water (50 mL), brine (50mL), dried over magnesium sulfate and concentrated. The residue wasdissolved in methylene chloride (5 mL), and 2,5-dioxopyrrolidin-1-yl2-(trimethylsilyl)ethyl carbonate (0.848 g) was added. After 1 hour, thereaction was quenched by the addition of water. The layers wereseparated, and the organic layer was dried with magnesium sulfate,filtered and concentrated. The residue was purified by silica gelchromatography, eluting with hexane/ethyl acetate, to give the titleproduct.

Example 185E6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,3-dimethyl-1-[2-(methylamino)ethoxy]cyclohexyl}methyl)-5-methyl-1H-pyrazol-4-yl]pyridine-2-carboxylicacid

A mixture of EXAMPLE 30A (0.629 g), EXAMPLE 185D (0.430 g),1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (0.125 g),potassium phosphate (0.908 g) andtris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.089 g) wasdissolved in tetrahydrofuran (3 mL) and water (1 mL). The reactionvessel was flushed with nitrogen and then heated under microwaveconditions (Biotage) to 140° C. for 5 minutes. The reaction mixture wasdiluted with ether (25 mL), washed with saturated NH₄Cl solution (20 mL)and brine (20 mL), dried over magnesium sulfate, filtered, andconcentrated. Purification of the residue by silica gel chromatography,eluting with a gradient of 5% to 100% ethyl acetate in hexanes, gave anintermediate ester. The residue was dissolved in methylene chloride (1mL), and TFA (1 mL) was added. After stirring overnight, the reactionmixture was concentrated and purified by RP-HPLC, eluting with 10-80%acetonitrile in water containing 0.1% v/v TFA, to give the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 12.85 (s, 1H), 8.70(s, 2H), 8.03 (d, J=7.8, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54-7.41 (m,4H), 7.36 (m, 2H), 6.97 (d, 1H), 4.97 (s, 2H), 4.06 (s, 2H), 3.90 (t,2H), 3.74 (m, 2H), 3.12 (s, 2H), 3.02 (t, 2H), 2.65 (t, 3H), 2.14 (s,3H), 1.35 (m, 8H), 0.97 (s, 3H), 0.86 (s, 3H).

Example 1866-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid Example 186A2,6-dimethyl-1-(5-methyl-1H-pyrazol-1-yl)hept-5-en-2-ol

The title compound was prepared by substituting 6-methylhept-5-en-2-onefor 3,3-dimethylcyclohexanone in EXAMPLE 185A.

Example 186B5-methyl-1-((2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole

A mixture of EXAMPLE 186A (6.5 g) and formic acid (20 mL) was heated at100° C. for 3 hours. The reaction mixture was concentrated, and theresidue was purified by silica gel chromatography, eluting with 1% ethylacetate in petroleum ether, to give the title product.

Example 186C4-bromo-5-methyl-1-((2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 186B for EXAMPLE63B in EXAMPLE 63C.

Example 186D5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazole

The title compound was prepared by substituting EXAMPLE 186C for EXAMPLE84C in EXAMPLE 84D.

Example 186E tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(5-methyl-1-((2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl)-1H-pyrazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 186D for EXAMPLE82D in EXAMPLE 82E.

Example 186F6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{5-methyl-1-[(2,6,6-trimethyltetrahydro-2H-pyran-2-yl)methyl]-1H-pyrazol-4-yl}pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 186E for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.84 (vbr s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.45 (m, 3H), 7.36(m, 2H), 7.27 (s, 1H), 6.96 (d, 1H), 4.95 (s, 2H), 4.00 (d, 2H), 3.88(br t, 2H), 3.01 (br t, 2H), 2.16 (s, 3H), 1.69 (m, 1H), 1.52 (m, 2H),1.39 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.07 (m, 1H), 1.06 (s, 3H).

Example 1876-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-4-yl)pyridine-2-carboxylicacid Example 187A1-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

The title compound was prepared by substituting4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole for4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and benzylbromide for EXAMPLE 4A in EXAMPLE 4B.

Example 187B tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-indazol-4-yl)picolinate

The title compound was prepared by substituting EXAMPLE 187A for EXAMPLE22A in EXAMPLE 22B.

Example 187C6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-4-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 187B for EXAMPLE1E in EXAMPLE 1F. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 12.89 (vbr s, 1H), 8.03 (d, 1H), 7.87 (s, 1H), 7.78 (m, 2H), 7.64 (m, 2H), 7.46(m, 2H), 7.40-7.20 (m, 8H), 7.04 (d, 1H), 6.99 (d, 1H), 5.66 (s, 2H),5.02 (s, 2H), 3.95 (br t, 2H), 3.04 (br t, 2H).

Example 1886-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylicacid Example 188A 1-benzyl-3-bromo-1H-pyrrolo[2,3-c]pyridine

The title compound was prepared by substituting3-bromo-1H-pyrrolo[2,3-c]pyridine for 3-bromo-1H-pyrrolo[2,3-b]pyridinein EXAMPLE 141A.

Example 188B1-benzyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-c]pyridine

The title compound was prepared by substituting EXAMPLE 188A for EXAMPLE84C in EXAMPLE 84D.

Example 188C tert-butyl6-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)picolinate

The title compound was prepared by substituting EXAMPLE 188B for EXAMPLE22A in EXAMPLE 22B.

Example 188D6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylicacid

The title compound was prepared by substituting EXAMPLE 188C for EXAMPLE8B in EXAMPLE 8C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ ppm 9.42 (s,1H), 8.47 (s, 1H), 8.32 (d, 1H), 8.04 (d, 1H), 7.89 (d, 1H), 7.79 (d,1H), 7.76 (d, 1H), 7.64 (br d, 1H), 7.48 (m, 2H), 7.40-7.28 (m, 7H),7.01 (d, 1H), 5.76 (s, 2H), 5.04 (s, 2H), 3.95 (br t, 2H), 3.05 (br t,2H).

What is claimed is:
 1. A compound or therapeutically acceptable saltthereof, wherein the compound is selected from the group consisting of6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-phenyl-1H-pyrazol-4-yl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-nitrophenoxy)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(4-chlorophenoxy)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(3-benzylphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethyl)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(4-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-5-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-4-phenoxyphenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[4-(cyclohexylmethoxy)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-cyano-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-chloro-3-(cyclohexyloxy)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexylamino)-2-methylphenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-fluorophenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[3-(cyclohexyloxy)-2-(trifluoromethyl)phenyl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)oxy]-2-methylphenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzoyl-1H-pyrrol-3-yl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-(phenylsulfonyl)-1H-pyrrol-3-yl]pyridine-2-carboxylicacid;6,6′-bis[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3,3′-bipyridine-2,2′-dicarboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-benzyl-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3′-methyl-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-(cyclohexyloxy)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-phenoxy-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-[methyl(phenyl)amino]-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-5-yl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-methyl-3-[methyl(phenyl)amino]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(3,3-dimethylcyclohexyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2′-[cyclohexyl(methyl)amino]-3′-methyl-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-cyano-2′-[cyclohexyl(methyl)amino]-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{3-[(cyclohexylcarbonyl)(methyl)amino]-2-methylphenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(2-methyl-3-{methyl[(1-methylcyclohexyl)carbonyl]amino}phenyl)pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[(cyclohexylsulfonyl)(methyl)amino]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{2-cyano-3-[2-(tricyclo[3.3.1.1^(3,7)]dec-1-yl)pyrrolidin-1-yl]phenyl}pyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3′-methyl-2′-(piperidin-1-yl)-3,4′-bipyridine-2-carboxylicacid;6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-indazol-4-yl)pyridine-2-carboxylicacid; and6-[8-(1,3-benzothiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-(1-benzyl-1H-pyrrolo[2,3-c]pyridin-3-yl)pyridine-2-carboxylicacid.
 2. A composition comprising a pharmaceutically acceptableexcipient and a therapeutically effective amount of the compound ortherapeutically acceptable salt of claim 1.